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Kim JY, Furney A, Benner B, Sengupta A. Stress-induced changes in endogenous TP53 mRNA 5' regulatory region. J Biol Chem 2025:108418. [PMID: 40113043 DOI: 10.1016/j.jbc.2025.108418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 03/11/2025] [Accepted: 03/14/2025] [Indexed: 03/22/2025] Open
Abstract
Tumor suppressor protein p53 is regulated in a number of ways, including during initiation of TP53 mRNA translation. The 5' end of TP53 mRNA contains regulatory structures that enable non-canonical initiation using mechanisms that remain poorly described. Here we analyze per-nucleotide reactivity changes in the 5' end secondary structure of TP53 mRNA under in-cell conditions using A549 human lung carcinoma cells. We first construct a cell-free secondary structure model using SHAPE reagent 5NIA (5-nitroisatoic anhydride) on gently extracted and deproteinated RNA. We observe previously described regulatory features of the TP53 mRNA 5' end including two motifs which we refer to as long stem-loop (LSL) and short stem-loop (SSL), respectively. We observe a domain-forming helix that groups LSL and SSL, forming a three-helix junction. Applying in-cell SHAPE-MaP, we assess reactivity profiles with unstressed cells and with chemically induced stress conditions expected to stimulate TP53 cap-independent translation. We analyze the effects of etoposide-induced DNA damage, CoCl2-induced hypoxia, and 5' cap inhibition with 4EGI-1 treatment. Identifying stress-associated changes in the TP53 5' end may help elucidate the role of regulatory RNA structure in cap-independent translation. Using ΔSHAPE we identify in-cell protection sites that correspond with previously described RNA-protein binding sites on the apical loops of LSL and SSL. Furthermore, we identify several other potential interaction sites, some associated with specific types of stress. Some noteworthy changes include ΔSHAPE sites proximal to the start codons, at the three-helix junction, and on the domain-forming helix. We summarize potential interactions on the cell-free secondary structure model.
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Affiliation(s)
- Jin Yeong Kim
- Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, GA, 31061, USA
| | - Alexandra Furney
- Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, GA, 31061, USA
| | - Brittany Benner
- Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, GA, 31061, USA
| | - Arnab Sengupta
- Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, GA, 31061, USA.
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2
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Zhao Z, Ruan S, Li Y, Qi T, Qi Y, Huang Y, Liu Z, Ruan Q, Ma Y. The Influence of Extra-Ribosomal Functions of Eukaryotic Ribosomal Proteins on Viral Infection. Biomolecules 2024; 14:1565. [PMID: 39766272 PMCID: PMC11674327 DOI: 10.3390/biom14121565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/25/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
The eukaryotic ribosome is a large ribonucleoprotein complex consisting of four types of ribosomal RNA (rRNA) and approximately 80 ribosomal proteins (RPs), forming the 40S and 60S subunits. In all living cells, its primary function is to produce proteins by converting messenger RNA (mRNA) into polypeptides. In addition to their canonical role in protein synthesis, RPs are crucial in controlling vital cellular processes such as cell cycle progression, cellular proliferation, differentiation, DNA damage repair, genome structure maintenance, and the cellular stress response. Viruses, as obligate intracellular parasites, depend completely on the machinery of the host cell for their replication and survival. During viral infection, RPs have been demonstrated to perform a variety of extra-ribosomal activities, which are especially important in viral disease processes. These functions cover a wide range of activities, ranging from controlling inflammatory responses and antiviral immunity to promoting viral replication and increasing viral pathogenicity. Deciphering the regulatory mechanisms used by RPs in response to viral infections has greatly expanded our understanding of their functions outside of the ribosome. Furthermore, these findings highlight the promising role of RPs as targets for the advancement of antiviral therapies and the development of novel antiviral approaches. This review comprehensively examines the many functions of RPs outside of the ribosome during viral infections and provides a foundation for future research on the host-virus interaction.
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Affiliation(s)
- Zhongwei Zhao
- Virology Laboratory, Shengjing Hospital of China Medical University, Shenyang 110004, China; (Z.Z.); (T.Q.); (Y.Q.); (Y.H.); (Z.L.)
| | - Shan Ruan
- Department of Gerontology, and Geriatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China;
| | - Yang Li
- Department of Blood Transfusion, Shengjing Hospital of China Medical University, Shenyang 110004, China;
| | - Te Qi
- Virology Laboratory, Shengjing Hospital of China Medical University, Shenyang 110004, China; (Z.Z.); (T.Q.); (Y.Q.); (Y.H.); (Z.L.)
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
- Departments of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Ying Qi
- Virology Laboratory, Shengjing Hospital of China Medical University, Shenyang 110004, China; (Z.Z.); (T.Q.); (Y.Q.); (Y.H.); (Z.L.)
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
- Departments of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yujing Huang
- Virology Laboratory, Shengjing Hospital of China Medical University, Shenyang 110004, China; (Z.Z.); (T.Q.); (Y.Q.); (Y.H.); (Z.L.)
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
- Departments of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Zhongyang Liu
- Virology Laboratory, Shengjing Hospital of China Medical University, Shenyang 110004, China; (Z.Z.); (T.Q.); (Y.Q.); (Y.H.); (Z.L.)
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
- Departments of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Qiang Ruan
- Virology Laboratory, Shengjing Hospital of China Medical University, Shenyang 110004, China; (Z.Z.); (T.Q.); (Y.Q.); (Y.H.); (Z.L.)
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
- Departments of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yanping Ma
- Virology Laboratory, Shengjing Hospital of China Medical University, Shenyang 110004, China; (Z.Z.); (T.Q.); (Y.Q.); (Y.H.); (Z.L.)
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
- Departments of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
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Khawar MB, Yu S, Afzal A, Sun H. Unraveling the complex landscape of endocrine resistance in breast cancer: Emerging role of long noncoding RNA AGPG and beyond. Chin Med J (Engl) 2024; 137:1985-1987. [PMID: 39033392 PMCID: PMC11332697 DOI: 10.1097/cm9.0000000000003228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Indexed: 07/23/2024] Open
Affiliation(s)
- Muhammad Babar Khawar
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China
- Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, Jiangsu 225001, China
- Applied Molecular Biology and Biomedicine Lab, Department of Zoology, University of Narowal, Narowal 51600, Pakistan
| | - Shiyi Yu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China
- Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Ali Afzal
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences Technology, University of Central Punjab, Lahore 54000, Pakistan
| | - Haibo Sun
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China
- Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, Jiangsu 225001, China
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4
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Fellmann F, Saunders C, O’Donohue MF, Reid DW, McFadden KA, Montel-Lehry N, Yu C, Fang M, Zhang J, Royer-Bertrand B, Farinelli P, Karboul N, Willer JR, Fievet L, Bhuiyan ZA, Kleinhenz AL, Jadeau J, Fulbright J, Rivolta C, Renella R, Katsanis N, Beckmann JS, Nicchitta CV, Da Costa L, Davis EE, Gleizes PE. An atypical form of 60S ribosomal subunit in Diamond-Blackfan anemia linked to RPL17 variants. JCI Insight 2024; 9:e172475. [PMID: 39088281 PMCID: PMC11385091 DOI: 10.1172/jci.insight.172475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/25/2024] [Indexed: 08/03/2024] Open
Abstract
Diamond-Blackfan anemia syndrome (DBA) is a ribosomopathy associated with loss-of-function variants in more than 20 ribosomal protein (RP) genes. Here, we report the genetic, functional, and biochemical dissection of 2 multigenerational pedigrees with variants in RPL17, a large ribosomal subunit protein-encoding gene. Affected individuals had clinical features and erythroid proliferation defects consistent with DBA. Further, RPL17/uL22 depletion resulted in anemia and micrognathia in zebrafish larvae, and in vivo complementation studies indicated that RPL17 variants were pathogenic. Lymphoblastoid cell lines (LCLs) derived from patients displayed a ribosomal RNA maturation defect reflecting haploinsufficiency of RPL17. The proteins encoded by RPL17 variants were not incorporated into ribosomes, but 10%-20% of 60S ribosomal subunits contained a short form of 5.8S rRNA (5.8SC), a species that is marginal in normal cells. These atypical 60S subunits were actively engaged in translation. Ribosome profiling showed changes of the translational profile, but those are similar to LCLs bearing RPS19 variants. These results link an additional RP gene to DBA. They show that ribosomes can be modified substantially by RPL17 haploinsufficiency but support the paradigm that translation alterations in DBA are primarily related to insufficient ribosome production rather than to changes in ribosome structure or composition.
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Affiliation(s)
- Florence Fellmann
- The ColLaboratory, University of Lausanne, Lausanne, Switzerland
- Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
| | - Carol Saunders
- University of Missouri Kansas City, School of Medicine, Kansas City, Missouri, USA
- Department of Pathology and Laboratory Medicine, Children’s Mercy Hospital, Kansas City, Missouri, USA
| | | | - David W. Reid
- Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA
| | - Kelsey A. McFadden
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA
| | - Nathalie Montel-Lehry
- MCD, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Cong Yu
- BGI-Shenzhen, Shenzhen, China
| | | | | | | | - Pietro Farinelli
- Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
| | | | - Jason R. Willer
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA
| | - Lorraine Fievet
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA
| | - Zahurul Alam Bhuiyan
- Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
| | - Alissa L.W. Kleinhenz
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA
| | - Julie Jadeau
- MCD, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Joy Fulbright
- Division of Hematology/Oncology, Children’s Mercy Hospital and Clinics, Kansas City, Missouri, USA
| | - Carlo Rivolta
- Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
| | - Raffaele Renella
- Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
| | - Nicholas Katsanis
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA
| | - Jacques S. Beckmann
- Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
- Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
- Clinical Bioinformatics, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Christopher V. Nicchitta
- Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Lydie Da Costa
- AP-HP, Service d’Hématologie Biologique, Hôpital Robert Debré, Paris, France
- Université Paris Cité, Paris, France
- Hematim EA4666, CURS, CHU Amiens, Amiens, France
- LABEX GR-EX, Paris, France
| | - Erica E. Davis
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA
- Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
- Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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Ikliptikawati DK, Makiyama K, Hazawa M, Wong RW. Unlocking the Gateway: The Spatio-Temporal Dynamics of the p53 Family Driven by the Nuclear Pores and Its Implication for the Therapeutic Approach in Cancer. Int J Mol Sci 2024; 25:7465. [PMID: 39000572 PMCID: PMC11242911 DOI: 10.3390/ijms25137465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/03/2024] [Accepted: 07/04/2024] [Indexed: 07/16/2024] Open
Abstract
The p53 family remains a captivating focus of an extensive number of current studies. Accumulating evidence indicates that p53 abnormalities rank among the most prevalent in cancer. Given the numerous existing studies, which mostly focus on the mutations, expression profiles, and functional perturbations exhibited by members of the p53 family across diverse malignancies, this review will concentrate more on less explored facets regarding p53 activation and stabilization by the nuclear pore complex (NPC) in cancer, drawing on several studies. p53 integrates a broad spectrum of signals and is subject to diverse regulatory mechanisms to enact the necessary cellular response. It is widely acknowledged that each stage of p53 regulation, from synthesis to degradation, significantly influences its functionality in executing specific tasks. Over recent decades, a large body of data has established that mechanisms of regulation, closely linked with protein activation and stabilization, involve intricate interactions with various cellular components. These often transcend canonical regulatory pathways. This new knowledge has expanded from the regulation of genes themselves to epigenomics and proteomics, whereby interaction partners increase in number and complexity compared with earlier paradigms. Specifically, studies have recently shown the involvement of the NPC protein in such complex interactions, underscoring the further complexity of p53 regulation. Furthermore, we also discuss therapeutic strategies based on recent developments in this field in combination with established targeted therapies.
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Affiliation(s)
- Dini Kurnia Ikliptikawati
- Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan;
| | - Kei Makiyama
- Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
| | - Masaharu Hazawa
- Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan;
- Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
- WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
| | - Richard W. Wong
- Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan;
- Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
- WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
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Zhou Y, Nakajima R, Shirasawa M, Fikriyanti M, Zhao L, Iwanaga R, Bradford AP, Kurayoshi K, Araki K, Ohtani K. Expanding Roles of the E2F-RB-p53 Pathway in Tumor Suppression. BIOLOGY 2023; 12:1511. [PMID: 38132337 PMCID: PMC10740672 DOI: 10.3390/biology12121511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023]
Abstract
The transcription factor E2F links the RB pathway to the p53 pathway upon loss of function of pRB, thereby playing a pivotal role in the suppression of tumorigenesis. E2F fulfills a major role in cell proliferation by controlling a variety of growth-associated genes. The activity of E2F is controlled by the tumor suppressor pRB, which binds to E2F and actively suppresses target gene expression, thereby restraining cell proliferation. Signaling pathways originating from growth stimulative and growth suppressive signals converge on pRB (the RB pathway) to regulate E2F activity. In most cancers, the function of pRB is compromised by oncogenic mutations, and E2F activity is enhanced, thereby facilitating cell proliferation to promote tumorigenesis. Upon such events, E2F activates the Arf tumor suppressor gene, leading to activation of the tumor suppressor p53 to protect cells from tumorigenesis. ARF inactivates MDM2, which facilitates degradation of p53 through proteasome by ubiquitination (the p53 pathway). P53 suppresses tumorigenesis by inducing cellular senescence or apoptosis. Hence, in almost all cancers, the p53 pathway is also disabled. Here we will introduce the canonical functions of the RB-E2F-p53 pathway first and then the non-classical functions of each component, which may be relevant to cancer biology.
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Affiliation(s)
- Yaxuan Zhou
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Rinka Nakajima
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Mashiro Shirasawa
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Mariana Fikriyanti
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Lin Zhao
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Ritsuko Iwanaga
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO 80045, USA; (R.I.); (A.P.B.)
| | - Andrew P. Bradford
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO 80045, USA; (R.I.); (A.P.B.)
| | - Kenta Kurayoshi
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan;
| | - Keigo Araki
- Department of Morphological Biology, Ohu University School of Dentistry, 31-1 Misumido Tomitamachi, Koriyama, Fukushima 963-8611, Japan;
| | - Kiyoshi Ohtani
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
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7
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Gong D, Rao X, Min Z, Liu X, Xin H, Zhou P, Yang L, Li D. UBE2S targets RPL26 for ubiquitination and degradation to promote non-small cell lung cancer progression via regulating c-Myc. Am J Cancer Res 2023; 13:3705-3720. [PMID: 37693154 PMCID: PMC10492117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 08/03/2023] [Indexed: 09/12/2023] Open
Abstract
Multiple studies have shown that E2 conjugating enzyme family are dysregulated in various cancers and associated with tumor progression and poor prognosis. In present study, we screened and confirmed that UBE2S is one of the E2 conjugating enzymes highly expressed in non-small cell lung cancer (NSCLC), and it plays an oncogenic role by enhancing cell proliferation, migration and stemness in vitro. Using immunoprecipitation technology combined with mass spectrometry assay, we identified ribosomal protein RPL26 as the substrate protein of UBE2S in NSCLC. At the molecular level, overexpression of UBE2S accelerated the ubiquitination and degradation of RPL26, thus upregulating c-Myc to enhance the progression of NSCLC. In addition, the results of a xenograft experiment showed that inhibiting UBE2S could suppress RPL26-c-Myc mediated NSCLC tumor growth in vivo. Our data provided mechanistic evidence supporting the existence of a novel UBE2S-RPL26-c-Myc axis and its critical contribution to progression of NSCLC.
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Affiliation(s)
- Dalian Gong
- Department of Life Science, College of Biology, Hunan UniversityChangsha 410012, Hunan, China
| | - Xinxu Rao
- Department of Life Science, College of Biology, Hunan UniversityChangsha 410012, Hunan, China
| | - Ziqian Min
- Department of Life Science, College of Biology, Hunan UniversityChangsha 410012, Hunan, China
| | - Xiaowen Liu
- Department of Life Science, College of Biology, Hunan UniversityChangsha 410012, Hunan, China
| | - Huan Xin
- Department of Life Science, College of Biology, Hunan UniversityChangsha 410012, Hunan, China
| | - Peijun Zhou
- Cancer Research Institute, Xiangya School of Medicine, Central South UniversityChangsha 410078, Hunan, China
| | - Lifang Yang
- Cancer Research Institute, Xiangya School of Medicine, Central South UniversityChangsha 410078, Hunan, China
| | - Dan Li
- Department of Life Science, College of Biology, Hunan UniversityChangsha 410012, Hunan, China
- Shenzhen Research Institute of Hunan UniversityShenzhen 518000, Guangdong, China
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8
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Cook J, Greene ES, Ramser A, Mullenix G, Dridi JS, Liyanage R, Wideman R, Dridi S. Comparative- and network-based proteomic analysis of bacterial chondronecrosis with osteomyelitis lesions in broiler's proximal tibiae identifies new molecular signatures of lameness. Sci Rep 2023; 13:5947. [PMID: 37045932 PMCID: PMC10097873 DOI: 10.1038/s41598-023-33060-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 04/06/2023] [Indexed: 04/14/2023] Open
Abstract
Bacterial Chondronecrosis with Osteomyelitis (BCO) is a specific cause of lameness in commercial fast-growing broiler (meat-type) chickens and represents significant economic, health, and wellbeing burdens. However, the molecular mechanisms underlying the pathogenesis remain poorly understood. This study represents the first comprehensive characterization of the proximal tibia proteome from healthy and BCO chickens. Among a total of 547 proteins identified, 222 were differentially expressed (DE) with 158 up- and 64 down-regulated proteins in tibia of BCO vs. normal chickens. Biological function analysis using Ingenuity Pathways showed that the DE proteins were associated with a variety of diseases including cell death, organismal injury, skeletal and muscular disorder, immunological and inflammatory diseases. Canonical pathway and protein-protein interaction network analysis indicated that these DE proteins were involved in stress response, unfolded protein response, ribosomal protein dysfunction, and actin cytoskeleton signaling. Further, we identified proteins involved in bone resorption (osteoclast-stimulating factor 1, OSFT1) and bone structural integrity (collagen alpha-2 (I) chain, COL2A1), as potential key proteins involved in bone attrition. These results provide new insights by identifying key protein candidates involved in BCO and will have significant impact in understanding BCO pathogenesis.
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Affiliation(s)
- Jennifer Cook
- Department of Poultry Science, University of Arkansas, 1260 W. Maple Street, Fayetteville, AR, 72701, USA
| | - Elizabeth S Greene
- Department of Poultry Science, University of Arkansas, 1260 W. Maple Street, Fayetteville, AR, 72701, USA
| | - Alison Ramser
- Department of Poultry Science, University of Arkansas, 1260 W. Maple Street, Fayetteville, AR, 72701, USA
| | - Garrett Mullenix
- Department of Poultry Science, University of Arkansas, 1260 W. Maple Street, Fayetteville, AR, 72701, USA
| | - Jalila S Dridi
- École Universitaire de Kinésithérapie, Université d'Orléans, Rue de Chartres, 45100, Orléans, France
| | - Rohana Liyanage
- Department of Poultry Science, University of Arkansas, 1260 W. Maple Street, Fayetteville, AR, 72701, USA
| | - Robert Wideman
- Department of Poultry Science, University of Arkansas, 1260 W. Maple Street, Fayetteville, AR, 72701, USA
| | - Sami Dridi
- Department of Poultry Science, University of Arkansas, 1260 W. Maple Street, Fayetteville, AR, 72701, USA.
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9
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McCann JJ, Fleenor DE, Chen J, Lai CH, Bass TE, Kastan MB. Participation of ATM, SMG1, and DDX5 in a DNA Damage-Induced Alternative Splicing Pathway. Radiat Res 2023; 199:406-421. [PMID: 36921295 PMCID: PMC10162594 DOI: 10.1667/rade-22-00219.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 02/03/2023] [Indexed: 03/17/2023]
Abstract
Altered cellular responses to DNA damage can contribute to cancer development, progression, and therapeutic resistance. Mutations in key DNA damage response factors occur across many cancer types, and the DNA damage-responsive gene, TP53, is frequently mutated in a high percentage of cancers. We recently reported that an alternative splicing pathway induced by DNA damage regulates alternative splicing of TP53 RNA and further modulates cellular stress responses. Through damage-induced inhibition of the SMG1 kinase, TP53 pre-mRNA is alternatively spliced to generate TP53b mRNA and p53b protein is required for optimal induction of cellular senescence after ionizing radiation-induced DNA damage. Herein, we confirmed and extended these observations by demonstrating that the ATM protein kinase is required for repression of SMG1 kinase activity after ionizing radiation. We found that the RNA helicase and splicing factor, DDX5, interacts with SMG1, is required for alternative splicing of TP53 pre-mRNA to TP53b and TP53c mRNAs after DNA damage, and contributes to radiation-induced cellular senescence. Interestingly, the role of SMG1 in alternative splicing of p53 appears to be distinguishable from its role in regulating nonsense-mediated RNA decay. Thus, ATM, SMG1, and DDX5 participate in a DNA damage-induced alternative splicing pathway that regulates TP53 splicing and modulates radiation-induced cellular senescence.
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Affiliation(s)
- Jennifer J. McCann
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710
| | - Donald E. Fleenor
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710
| | - Jing Chen
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710
| | - Chun-Hsiang Lai
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710
| | - Thomas E. Bass
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710
| | - Michael B. Kastan
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710
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10
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Steffens Reinhardt L, Groen K, Newton C, Avery-Kiejda KA. The role of truncated p53 isoforms in the DNA damage response. Biochim Biophys Acta Rev Cancer 2023; 1878:188882. [PMID: 36977456 DOI: 10.1016/j.bbcan.2023.188882] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 02/23/2023] [Accepted: 02/25/2023] [Indexed: 03/28/2023]
Abstract
The tumour suppressor p53 is activated following genotoxic stress and regulates the expression of target genes involved in the DNA damage response (DDR). The discovery that p53 isoforms alter the transcription of p53 target genes or p53 protein interactions unveiled an alternative DDR. This review will focus on the role p53 isoforms play in response to DNA damage. The expression of the C-terminally truncated p53 isoforms may be modulated via DNA damage-induced alternative splicing, whereas alternative translation plays an important role in modulating the expression of N-terminally truncated isoforms. The DDR induced by p53 isoforms may enhance the canonical p53 DDR or block cell death mechanisms in a DNA damage- and cell-specific manner, which could contribute to chemoresistance in a cancer context. Thus, a better understanding of the involvement of p53 isoforms in the cell fate decisions could uncover potential therapeutic targets in cancer and other diseases.
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Affiliation(s)
- Luiza Steffens Reinhardt
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Kira Groen
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Cheryl Newton
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Kelly A Avery-Kiejda
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia.
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11
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Hannan KM, Soo P, Wong MS, Lee JK, Hein N, Poh P, Wysoke KD, Williams TD, Montellese C, Smith LK, Al-Obaidi SJ, Núñez-Villacís L, Pavy M, He JS, Parsons KM, Loring KE, Morrison T, Diesch J, Burgio G, Ferreira R, Feng ZP, Gould CM, Madhamshettiwar PB, Flygare J, Gonda TJ, Simpson KJ, Kutay U, Pearson RB, Engel C, Watkins NJ, Hannan RD, George AJ. Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway. Cell Rep 2022; 41:111571. [DOI: 10.1016/j.celrep.2022.111571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/06/2022] [Accepted: 10/06/2022] [Indexed: 11/06/2022] Open
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12
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Fefilova AS, Antifeeva IA, Gavrilova AA, Turoverov KK, Kuznetsova IM, Fonin AV. Reorganization of Cell Compartmentalization Induced by Stress. Biomolecules 2022; 12:1441. [PMID: 36291650 PMCID: PMC9599104 DOI: 10.3390/biom12101441] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/30/2022] [Accepted: 10/01/2022] [Indexed: 11/17/2022] Open
Abstract
The discovery of intrinsically disordered proteins (IDPs) that do not have an ordered structure and nevertheless perform essential functions has opened a new era in the understanding of cellular compartmentalization. It threw the bridge from the mostly mechanistic model of the organization of the living matter to the idea of highly dynamic and functional "soft matter". This paradigm is based on the notion of the major role of liquid-liquid phase separation (LLPS) of biopolymers in the spatial-temporal organization of intracellular space. The LLPS leads to the formation of self-assembled membrane-less organelles (MLOs). MLOs are multicomponent and multifunctional biological condensates, highly dynamic in structure and composition, that allow them to fine-tune the regulation of various intracellular processes. IDPs play a central role in the assembly and functioning of MLOs. The LLPS importance for the regulation of chemical reactions inside the cell is clearly illustrated by the reorganization of the intracellular space during stress response. As a reaction to various types of stresses, stress-induced MLOs appear in the cell, enabling the preservation of the genetic and protein material during unfavourable conditions. In addition, stress causes structural, functional, and compositional changes in the MLOs permanently present inside the cells. In this review, we describe the assembly of stress-induced MLOs and the stress-induced modification of existing MLOs in eukaryotes, yeasts, and prokaryotes in response to various stress factors.
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Affiliation(s)
| | | | | | - Konstantin K. Turoverov
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology of RAS, 194064 St. Petersburg, Russia
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13
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Zhang Z, He G, Lv Y, Liu Y, Niu Z, Feng Q, Hu R, Xu J. HERC3 regulates epithelial-mesenchymal transition by directly ubiquitination degradation EIF5A2 and inhibits metastasis of colorectal cancer. Cell Death Dis 2022; 13:74. [PMID: 35064108 PMCID: PMC8782983 DOI: 10.1038/s41419-022-04511-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 12/12/2021] [Accepted: 12/30/2021] [Indexed: 12/21/2022]
Abstract
E3 ligase is widely reported to exert fundamental functions in cancers. Through rigorous bioinformatic analysis concentrating E3 ligases based on data from Genotype-Tissue Expression (GTEx) and data from The Cancer Genome Atlas (TCGA), HERC3 was indicated to be downregulated in colorectal cancer (CRC) and HERC3 downregulation showed poor overall survival (OS) and disease-free survival (DFS). Through qRT-PCR, western blotting and Immunohistochemistry (IHC), analytical results were validated based on tissues in Zhongshan hospital. Functionally, HERC3 was indicated to inhibit the migration, invasion and metastasis in vitro and in vivo through transwell assays, wound healing assays and vivo experiments. And HERC3 could regulate epithelial-mesenchymal transition (EMT) in CRC. Furthermore, immunoprecipitation (IP), coimmunoprecipitation (co-IP) and GST-pulldown assays indicated that HERC3 could directly interact with EIF5A2 in vitro and in vivo through the RCC1 domain in HERC3. And HERC3 could function as an E3 to promote the K27 and K48-linked ubiquitination degradation of EIF5A2 via the HECT domain in HERC3, besides, K47, K67, K85, and K121 in EIF5A2 were identified as ubiquitination sites. In addition, HERC3 was indicated to affect the migration, invasion and metastasis and further regulatE EMT via EIF5A2/TGF-/Smad2/3 signal. The present study may provide insight into the mechanism of EMT in CRC.
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Affiliation(s)
- Zhiyuan Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University, 200030, Shanghai, China
| | - Guodong He
- Department of General Surgery, Zhongshan Hospital, Fudan University, 200030, Shanghai, China
| | - Yang Lv
- Department of General Surgery, Zhongshan Hospital, Fudan University, 200030, Shanghai, China
| | - Yu Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, 200030, Shanghai, China
| | - Zhengchuan Niu
- Department of General Surgery, Zhongshan Hospital, Fudan University, 200030, Shanghai, China
| | - Qingyang Feng
- Department of General Surgery, Zhongshan Hospital, Fudan University, 200030, Shanghai, China
| | - Ronggui Hu
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, 200030, Shanghai, China.
| | - Jianmin Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, 200030, Shanghai, China.
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14
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Wang C, Yang Y, Wu X, Li J, Liu K, Fang D, Li B, Shan G, Mei X, Wang F, Mei Y. Reciprocal modulation of long noncoding RNA EMS and p53 regulates tumorigenesis. Proc Natl Acad Sci U S A 2022; 119:e2111409119. [PMID: 35022235 PMCID: PMC8784137 DOI: 10.1073/pnas.2111409119] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
p53 plays a central role in tumor suppression. Emerging evidence suggests long noncoding RNA (lncRNA) as an important class of regulatory molecules that control the p53 signaling. Here, we report that the oncogenic lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and p53 mutually repress each other's expression. EMS is negatively regulated by p53. As a direct transcriptional repression target of p53, EMS is surprisingly shown to inhibit p53 expression. EMS associates with cytoplasmic polyadenylation element-binding protein 2 (CPEB2) and thus, disrupts the CPEB2-p53 mRNA interaction. This disassociation attenuates CPEB2-mediated p53 mRNA polyadenylation and suppresses p53 translation. Functionally, EMS is able to exert its oncogenic activities, at least partially, via the CPEB2-p53 axis. Together, these findings reveal a double-negative feedback loop between p53 and EMS, through which p53 is finely controlled. Our study also demonstrates a critical role for EMS in promoting tumorigenesis via the negative regulation of p53.
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Affiliation(s)
- Chenfeng Wang
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Yang Yang
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Xianning Wu
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Jingxin Li
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Kaiyue Liu
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Debao Fang
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Bingyan Li
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Ge Shan
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Xinyu Mei
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China;
| | - Fang Wang
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China;
| | - Yide Mei
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China;
- The Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei 230027, China
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15
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The Identification and Validation of Hub Genes Associated with Acute Myocardial Infarction Using Weighted Gene Co-Expression Network Analysis. J Cardiovasc Dev Dis 2022; 9:jcdd9010030. [PMID: 35050240 PMCID: PMC8778825 DOI: 10.3390/jcdd9010030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/08/2022] [Accepted: 01/12/2022] [Indexed: 02/06/2023] Open
Abstract
Acute myocardial infarction (AMI), one of the most severe and fatal cardiovascular diseases, remains the main cause of mortality and morbidity worldwide. The objective of this study is to investigate the potential biomarkers for AMI based on bioinformatics analysis. A total of 2102 differentially expressed genes (DEGs) were screened out from the data obtained from the gene expression omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) explored the co-expression network of DEGs and determined the key module. The brown module was selected as the key one correlated with AMI. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses demonstrated that genes in the brown module were mainly enriched in ‘ribosomal subunit’ and ‘Ribosome’. Gene Set Enrichment Analysis revealed that ‘TNFA_SIGNALING_VIA_NFKB’ was remarkably enriched in AMI. Based on the protein–protein interaction network, ribosomal protein L9 (RPL9) and ribosomal protein L26 (RPL26) were identified as the hub genes. Additionally, the polymerase chain reaction (PCR) results indicated that the expression levels of RPL9 and RPL26 were both downregulated in AMI patients compared with controls, in accordance with the bioinformatics analysis. In summary, the identified DEGs, modules, pathways, and hub genes provide clues and shed light on the potential molecular mechanisms of AMI.
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16
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Ji L, Chen S, Gu G, Wang W, Ren J, Xu F, Li F, Wu J, Yang D, Zheng Y. Discovery of potential biomarkers for human atherosclerotic abdominal aortic aneurysm through untargeted metabolomics and transcriptomics. J Zhejiang Univ Sci B 2021; 22:733-745. [PMID: 34514753 DOI: 10.1631/jzus.b2000713] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Abdominal aortic aneurysm (AAA) and atherosclerosis (AS) have considerable similarities in clinical risk factors and molecular pathogenesis. The aim of our study was to investigate the differences between AAA and AS from the perspective of metabolomics, and to explore the potential mechanisms of differential metabolites via integration analysis with transcriptomics. Plasma samples from 32 AAA and 32 AS patients were applied to characterize the metabolite profiles using untargeted liquid chromatography-mass spectrometry (LC-MS). A total of 18 remarkably different metabolites were identified, and a combination of seven metabolites could potentially serve as a biomarker to distinguish AAA and AS, with an area under the curve (AUC) of 0.93. Subsequently, we analyzed both the metabolomics and transcriptomics data and found that seven metabolites, especially 2'-deoxy-D-ribose (2dDR), were significantly correlated with differentially expressed genes. In conclusion, our study presents a comprehensive landscape of plasma metabolites in AAA and AS patients, and provides a research direction for pathogenetic mechanisms in atherosclerotic AAA.
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Affiliation(s)
- Lei Ji
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Siliang Chen
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Guangchao Gu
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Wei Wang
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jinrui Ren
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Fang Xu
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Fangda Li
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jianqiang Wu
- Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Dan Yang
- Department of Computational Biology and Bioinformatics, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Yuehong Zheng
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
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17
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Kang J, Brajanovski N, Chan KT, Xuan J, Pearson RB, Sanij E. Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy. Signal Transduct Target Ther 2021; 6:323. [PMID: 34462428 PMCID: PMC8405630 DOI: 10.1038/s41392-021-00728-8] [Citation(s) in RCA: 186] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 07/12/2021] [Accepted: 07/30/2021] [Indexed: 02/07/2023] Open
Abstract
Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation. The ribosomal proteins (RPs), comprising the structural parts of the ribosome, are essential for ribosome assembly and function. In addition to their canonical ribosomal functions, multiple RPs have extra-ribosomal functions including activation of p53-dependent or p53-independent pathways in response to stress, resulting in cell cycle arrest and apoptosis. Defects in ribosome biogenesis, translation, and the functions of individual RPs, including mutations in RPs have been linked to a diverse range of human congenital disorders termed ribosomopathies. Ribosomopathies are characterized by tissue-specific phenotypic abnormalities and higher cancer risk later in life. Recent discoveries of somatic mutations in RPs in multiple tumor types reinforce the connections between ribosomal defects and cancer. In this article, we review the most recent advances in understanding the molecular consequences of RP mutations and ribosomal defects in ribosomopathies and cancer. We particularly discuss the molecular basis of the transition from hypo- to hyper-proliferation in ribosomopathies with elevated cancer risk, a paradox termed "Dameshek's riddle." Furthermore, we review the current treatments for ribosomopathies and prospective therapies targeting ribosomal defects. We also highlight recent advances in ribosome stress-based cancer therapeutics. Importantly, insights into the mechanisms of resistance to therapies targeting ribosome biogenesis bring new perspectives into the molecular basis of cancer susceptibility in ribosomopathies and new clinical implications for cancer therapy.
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Affiliation(s)
- Jian Kang
- grid.1055.10000000403978434Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC Australia ,grid.1008.90000 0001 2179 088XSir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC Australia
| | - Natalie Brajanovski
- grid.1055.10000000403978434Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC Australia
| | - Keefe T. Chan
- grid.1055.10000000403978434Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC Australia ,grid.1008.90000 0001 2179 088XSir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC Australia
| | - Jiachen Xuan
- grid.1055.10000000403978434Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC Australia ,grid.1008.90000 0001 2179 088XSir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC Australia
| | - Richard B. Pearson
- grid.1055.10000000403978434Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC Australia ,grid.1008.90000 0001 2179 088XSir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC Australia ,grid.1002.30000 0004 1936 7857Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC Australia ,grid.1008.90000 0001 2179 088XDepartment of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC Australia
| | - Elaine Sanij
- grid.1055.10000000403978434Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC Australia ,grid.1008.90000 0001 2179 088XSir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC Australia ,grid.1008.90000 0001 2179 088XDepartment of Clinical Pathology, University of Melbourne, Melbourne, VIC Australia ,grid.1073.50000 0004 0626 201XSt. Vincent’s Institute of Medical Research, Fitzroy, VIC Australia
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18
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Abstract
The tumor suppressor p53 prevents tumorigenesis, while inactivation of p53 promotes cancer development and drug resistance. Here, we identify that a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), promotes growth and proliferation of colorectal cancer cells by inhibiting p53 activity. Mechanistically, RMRP retains SNRPA1 in the nucleus, thus preventing its lysosomal degradation. The nuclear SNRPA1 then prompts MDM2-mediated p53 ubiquitination and degradation. Remarkably, RMRP expression is induced by poly (ADP-ribose) polymerase (PARP) inhibitors, a group of targeted anticancer drugs, through the transcription factor C/EBPβ. Targeting RMRP significantly enhances sensitivity of colorectal cancer cells to PARP inhibition by reactivating p53. Our study provides a possible mechanism underling tumor resistance to PARP inhibitors. p53 inactivation is highly associated with tumorigenesis and drug resistance. Here, we identify a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), as an inhibitor of p53. RMRP is overexpressed and associated with an unfavorable prognosis in colorectal cancer. Ectopic RMRP suppresses p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while depletion of RMRP activates the p53 pathway. RMRP also promotes colorectal cancer growth and proliferation in a p53-dependent fashion in vitro and in vivo. This anti-p53 action of RMRP is executed through an identified partner protein, SNRPA1. RMRP can interact with SNRPA1 and sequester it in the nucleus, consequently blocking its lysosomal proteolysis via chaperone-mediated autophagy. The nuclear SNRPA1 then interacts with p53 and enhances MDM2-induced proteasomal degradation of p53. Remarkably, ablation of SNRPA1 completely abrogates RMRP regulation of p53 and tumor cell growth, indicating that SNRPA1 is indispensable for the anti-p53 function of RMRP. Interestingly and significantly, poly (ADP-ribose) polymerase (PARP) inhibitors induce RMRP expression through the transcription factor C/EBPβ, and RMRP confers tumor resistance to PARP inhibition by preventing p53 activation. Altogether, our study demonstrates that RMRP plays an oncogenic role by inactivating p53 via SNRPA1 in colorectal cancer.
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19
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Chen J, Zhang D, Qin X, Owzar K, McCann JJ, Kastan MB. DNA-Damage-Induced Alternative Splicing of p53. Cancers (Basel) 2021; 13:E251. [PMID: 33445417 PMCID: PMC7827558 DOI: 10.3390/cancers13020251] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/25/2020] [Accepted: 01/04/2021] [Indexed: 11/18/2022] Open
Abstract
Cellular responses to DNA damage and other stresses are important determinants of mutagenesis and impact the development of a wide range of human diseases. TP53 is highly mutated in human cancers and plays an essential role in stress responses and cell fate determination. A central dogma of p53 induction after DNA damage has been that the induction results from a transient increase in the half-life of the p53 protein. Our laboratory recently demonstrated that this long-standing paradigm is an incomplete picture of p53 regulation by uncovering a critical role for protein translational regulation in p53 induction after DNA damage. These investigations led to the discovery of a DNA-damage-induced alternative splicing (AS) pathway that affects p53 and other gene products. The damage-induced AS of p53 pre-mRNA generates the beta isoform of p53 (p53β) RNA and protein, which is specifically required for the induction of cellular senescence markers after ionizing irradiation (IR). In an attempt to elucidate the mechanisms behind the differential regulation and apparent functional divergence between full-length (FL) p53 and the p53β isoform (apoptosis versus senescence, respectively), we identified the differential transcriptome and protein interactome between these two proteins that may result from the unique 10-amino-acid tail in p53β protein.
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Affiliation(s)
- Jing Chen
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; (J.C.); (J.J.M.)
- Current Address-Crown Bioscience, Inc., San Diego, CA 92127, USA
| | - Dadong Zhang
- Duke Cancer Institute, Durham, NC 27710, USA; (D.Z.); (X.Q.); (K.O.)
| | - Xiaodi Qin
- Duke Cancer Institute, Durham, NC 27710, USA; (D.Z.); (X.Q.); (K.O.)
| | - Kouros Owzar
- Duke Cancer Institute, Durham, NC 27710, USA; (D.Z.); (X.Q.); (K.O.)
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA
| | - Jennifer J. McCann
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; (J.C.); (J.J.M.)
| | - Michael B. Kastan
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; (J.C.); (J.J.M.)
- Duke Cancer Institute, Durham, NC 27710, USA; (D.Z.); (X.Q.); (K.O.)
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20
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Karakostis K, Vadivel Gnanasundram S, López I, Thermou A, Wang L, Nylander K, Olivares-Illana V, Fåhraeus R. A single synonymous mutation determines the phosphorylation and stability of the nascent protein. J Mol Cell Biol 2020; 11:187-199. [PMID: 30252118 DOI: 10.1093/jmcb/mjy049] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 05/29/2018] [Accepted: 06/19/2018] [Indexed: 01/06/2023] Open
Abstract
p53 is an intrinsically disordered protein with a large number of post-translational modifications and interacting partners. The hierarchical order and subcellular location of these events are still poorly understood. The activation of p53 during the DNA damage response (DDR) requires a switch in the activity of the E3 ubiquitin ligase MDM2 from a negative to a positive regulator of p53. This is mediated by the ATM kinase that regulates the binding of MDM2 to the p53 mRNA facilitating an increase in p53 synthesis. Here we show that the binding of MDM2 to the p53 mRNA brings ATM to the p53 polysome where it phosphorylates the nascent p53 at serine 15 and prevents MDM2-mediated degradation of p53. A single synonymous mutation in p53 codon 22 (L22L) prevents the phosphorylation of the nascent p53 protein and the stabilization of p53 following genotoxic stress. The ATM trafficking from the nucleus to the p53 polysome is mediated by MDM2, which requires its interaction with the ribosomal proteins RPL5 and RPL11. These results show how the ATM kinase phosphorylates the p53 protein while it is being synthesized and offer a novel mechanism whereby a single synonymous mutation controls the stability and activity of the encoded protein.
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Affiliation(s)
- Konstantinos Karakostis
- Équipe Labellisée Ligue Contre le Cancer, Université Paris 7, INSERM UMR 1162, 27 Rue Juliette Dodu, Paris, France
| | | | - Ignacio López
- Équipe Labellisée Ligue Contre le Cancer, Université Paris 7, INSERM UMR 1162, 27 Rue Juliette Dodu, Paris, France
| | - Aikaterini Thermou
- Équipe Labellisée Ligue Contre le Cancer, Université Paris 7, INSERM UMR 1162, 27 Rue Juliette Dodu, Paris, France
| | - Lixiao Wang
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Karin Nylander
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | | | - Robin Fåhraeus
- Équipe Labellisée Ligue Contre le Cancer, Université Paris 7, INSERM UMR 1162, 27 Rue Juliette Dodu, Paris, France.,Department of Medical Biosciences, Umeå University, Umeå, Sweden.,RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, Czech Republic
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21
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Hao Q, Chen Y, Zhou X. The Janus Face of p53-Targeting Ubiquitin Ligases. Cells 2020; 9:cells9071656. [PMID: 32660118 PMCID: PMC7407405 DOI: 10.3390/cells9071656] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 12/11/2022] Open
Abstract
The tumor suppressor p53 prevents tumorigenesis and cancer progression by maintaining genomic stability and inducing cell growth arrest and apoptosis. Because of the extremely detrimental nature of wild-type p53, cancer cells usually mutate the TP53 gene in favor of their survival and propagation. Some of the mutant p53 proteins not only lose the wild-type activity, but also acquire oncogenic function, namely “gain-of-function”, to promote cancer development. Growing evidence has revealed that various E3 ubiquitin ligases are able to target both wild-type and mutant p53 for degradation or inactivation, and thus play divergent roles leading to cancer cell survival or death in the context of different p53 status. In this essay, we reviewed the recent progress in our understanding of the p53-targeting E3 ubiquitin ligases, and discussed the potential clinical implications of these E3 ubiquitin ligases in cancer therapy.
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Affiliation(s)
- Qian Hao
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
| | - Yajie Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China;
| | - Xiang Zhou
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
- Correspondence: ; Tel.: +86-21-54237325
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22
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Kaiser RWJ, Erber J, Höpker K, Fabretti F, Müller RU. AATF/Che-1-An RNA Binding Protein at the Nexus of DNA Damage Response and Ribosome Biogenesis. Front Oncol 2020; 10:919. [PMID: 32587828 PMCID: PMC7298124 DOI: 10.3389/fonc.2020.00919] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 05/11/2020] [Indexed: 01/14/2023] Open
Abstract
The DNA damage response (DDR) is a complex signaling network that is activated upon genotoxic stress. It determines cellular fate by either activating cell cycle arrest or initiating apoptosis and thereby ensures genomic stability. The Apoptosis Antagonizing Transcription Factor (AATF/Che-1), an RNA polymerase II-interacting transcription factor and known downstream target of major DDR kinases, affects DDR signaling by inhibiting p53-mediated transcription of pro-apoptotic genes and promoting cell cycle arrest through various pathways instead. Specifically, AATF was shown to inhibit p53 expression at the transcriptional level and repress its pro-apoptotic activity by direct binding to p53 protein and transactivation of anti-apoptotic genes. Solid and hematological tumors of various organs exploit this function by overexpressing AATF. Both copy number gains and high expression levels of AATF were associated with worse prognosis or relapse of malignant tumors. Recently, a number of studies have enabled insights into the molecular mechanisms by which AATF affects both DDR and proliferation. AATF was found to directly localize to sites of DNA damage upon laser ablation and interact with DNA repair proteins. In addition, depletion of AATF resulted in increased DNA damage and decrease of both proliferative activity and genotoxic tolerance. Interestingly, considering the role of ribosomal stress in the regulation of p53, more recent work established AATF as ribosomal RNA binding protein and enabled insights into its role as an important factor for rRNA processing and ribosome biogenesis. This Mini Review summarizes recent findings on AATF and its important role in the DDR, malignancy, and ribosome biogenesis.
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Affiliation(s)
- Rainer W J Kaiser
- Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian-University Munich, Munich, Germany.,Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Johanna Erber
- Department I of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.,Department of Medicine II, School of Medicine, Technical University of Munich, University Hospital Rechts der Isar, Munich, Germany
| | - Katja Höpker
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Francesca Fabretti
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Roman-Ulrich Müller
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.,Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany
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23
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Cho J, Park J, Shin SC, Jang M, Kim JH, Kim EE, Song EJ. USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2. Cancers (Basel) 2020; 12:E1137. [PMID: 32370049 PMCID: PMC7281321 DOI: 10.3390/cancers12051137] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 01/05/2023] Open
Abstract
p53 is activated in response to cellular stresses such as DNA damage, oxidative stress, and especially ribosomal stress. Although the regulations of p53 by E3 ligase and deubiquitinating enzymes (DUBs) have been described, the cellular roles of DUB associated with ribosomal stress have not been well studied. In this study, we report that Ubiquitin Specific Protease 47 (USP47) functions as an important regulator of p53. We show that ubiquitinated ribosomal protein S2 (RPS2) by Mouse double minute 2 homolog (MDM2) is deubiquitinated by USP47. USP47 inhibits the interaction between RPS2 and MDM2 thereby alleviating RPS2-mediated suppression of MDM2 under normal conditions. However, dissociation of USP47 leads to RPS2 binding to MDM2, which is required for the suppression of MDM2, consequently inducing up-regulation of the p53 level under ribosomal stress. Finally, we show that depletion of USP47 induces p53 and therefore inhibits cell proliferation, colony formation, and tumor progression in cancer cell lines and a mouse xenograft model. These findings suggest that USP47 could be a potential therapeutic target for cancer.
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Affiliation(s)
- Jinhong Cho
- Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea; (J.C.); (S.C.S.); (M.J.)
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul 02841, Korea;
| | - Jinyoung Park
- Molecular Recognition Research Center, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea;
| | - Sang Chul Shin
- Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea; (J.C.); (S.C.S.); (M.J.)
| | - Mihue Jang
- Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea; (J.C.); (S.C.S.); (M.J.)
| | - Jae-Hong Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul 02841, Korea;
| | - Eunice EunKyeong Kim
- Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea; (J.C.); (S.C.S.); (M.J.)
| | - Eun Joo Song
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Korea
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24
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Napoli M, Flores ER. The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer. RNA Biol 2020; 17:1636-1647. [PMID: 31910062 PMCID: PMC7567494 DOI: 10.1080/15476286.2019.1710054] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The tumour suppressor p53 and its paralogues, p63 and p73, are essential to maintain cellular homoeostasis and the integrity of the cell's genetic material, thus meriting the title of 'guardians of the genome'. The p53 family members are transcription factors and fulfill their activities by controlling the expression of protein-coding and non-coding genes. Here, we review how the latter group transcended from the 'dark matter' of the transcriptome, providing unexpected and intriguing anti-cancer therapeutic strategies.
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Affiliation(s)
- Marco Napoli
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL, USA.,Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL, USA
| | - Elsa R Flores
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL, USA.,Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL, USA
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25
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Sun X, Zhang R, Liu M, Chen H, Chen L, Luo F, Zhang D, Huang J, Li F, Ni Z, Qi H, Su N, Jin M, Yang J, Tan Q, Du X, Chen B, Huang H, Chen S, Yin L, Xu X, Deng C, Luo L, Xie Y, Chen L. Rmrp Mutation Disrupts Chondrogenesis and Bone Ossification in Zebrafish Model of Cartilage-Hair Hypoplasia via Enhanced Wnt/β-Catenin Signaling. J Bone Miner Res 2019; 34:2101-2116. [PMID: 31237961 DOI: 10.1002/jbmr.3820] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 06/11/2019] [Accepted: 06/14/2019] [Indexed: 01/09/2023]
Abstract
Cartilage-hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by bone dysplasia and many other highly variable features. The gene responsible for CHH is the RNA component of the mitochondrial RNA-processing endoribonuclease (RMRP) gene. Currently, the pathogenesis of osteochondrodysplasia and extraskeletal manifestations in CHH patients remains incompletely understood; in addition, there are no viable animal models for CHH. We generated an rmrp KO zebrafish model to study the developmental mechanisms of CHH. We found that rmrp is required for the patterning and shaping of pharyngeal arches. Rmrp mutation inhibits the intramembranous ossification of skull bones and promotes vertebrae ossification. The abnormalities of endochondral bone ossification are variable, depending on the degree of dysregulated chondrogenesis. Moreover, rmrp mutation inhibits cell proliferation and promotes apoptosis through dysregulating the expressions of cell-cycle- and apoptosis-related genes. We also demonstrate that rmrp mutation upregulates canonical Wnt/β-catenin signaling; the pharmacological inhibition of Wnt/β-catenin could partially alleviate the chondrodysplasia and increased vertebrae mineralization in rmrp mutants. Our study, by establishing a novel zebrafish model for CHH, partially reveals the underlying mechanism of CHH, hence deepening our understanding of the role of rmrp in skeleton development.
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Affiliation(s)
- Xianding Sun
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Ruobin Zhang
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Mi Liu
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Hangang Chen
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Liang Chen
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Fengtao Luo
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Dali Zhang
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Junlan Huang
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Fangfang Li
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Zhenhong Ni
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Huabing Qi
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Nan Su
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Min Jin
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Jing Yang
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Qiaoyan Tan
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Xiaolan Du
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Bo Chen
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Haiyang Huang
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Shuai Chen
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Liangjun Yin
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Xiaoling Xu
- Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Chuxia Deng
- Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Lingfei Luo
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, Chongqing, 400715, China
| | - Yangli Xie
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Lin Chen
- Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
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26
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Kaiser RWJ, Ignarski M, Van Nostrand EL, Frese CK, Jain M, Cukoski S, Heinen H, Schaechter M, Seufert L, Bunte K, Frommolt P, Keller P, Helm M, Bohl K, Höhne M, Schermer B, Benzing T, Höpker K, Dieterich C, Yeo GW, Müller RU, Fabretti F. A protein-RNA interaction atlas of the ribosome biogenesis factor AATF. Sci Rep 2019; 9:11071. [PMID: 31363146 PMCID: PMC6667500 DOI: 10.1038/s41598-019-47552-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 07/19/2019] [Indexed: 01/08/2023] Open
Abstract
AATF is a central regulator of the cellular outcome upon p53 activation, a finding that has primarily been attributed to its function as a transcription factor. Recent data showed that AATF is essential for ribosome biogenesis and plays a role in rRNA maturation. AATF has been implicated to fulfil this role through direct interaction with rRNA and was identified in several RNA-interactome capture experiments. Here, we provide a first comprehensive analysis of the RNA bound by AATF using CLIP-sequencing. Interestingly, this approach shows predominant binding of the 45S pre-ribosomal RNA precursor molecules. Furthermore, AATF binds to mRNAs encoding for ribosome biogenesis factors as well as snoRNAs. These findings are complemented by an in-depth analysis of the protein interactome of AATF containing a large set of proteins known to play a role in rRNA maturation with an emphasis on the protein-RNA-complexes known to be required for the generation of the small ribosomal subunit (SSU). In line with this finding, the binding sites of AATF within the 45S rRNA precursor localize in close proximity to the SSU cleavage sites. Consequently, our multilayer analysis of the protein-RNA interactome of AATF reveals this protein to be an important hub for protein and RNA interactions involved in ribosome biogenesis.
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Affiliation(s)
- Rainer W J Kaiser
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Michael Ignarski
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Eric L Van Nostrand
- Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
- Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Christian K Frese
- Proteomics Core Facility, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Manaswita Jain
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
| | - Sadrija Cukoski
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
| | - Heide Heinen
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
| | - Melanie Schaechter
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
| | - Lisa Seufert
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Konstantin Bunte
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
- Bioinformatics Core Facility, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Peter Frommolt
- Bioinformatics Core Facility, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Patrick Keller
- Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudingerweg 5, 55128, Mainz, Germany
| | - Mark Helm
- Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudingerweg 5, 55128, Mainz, Germany
| | - Katrin Bohl
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Martin Höhne
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
- Systems Biology of Ageing Cologne, University of Cologne, 50931, Cologne, Germany
| | - Bernhard Schermer
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
- Systems Biology of Ageing Cologne, University of Cologne, 50931, Cologne, Germany
| | - Thomas Benzing
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
- Systems Biology of Ageing Cologne, University of Cologne, 50931, Cologne, Germany
| | - Katja Höpker
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Christoph Dieterich
- German Center for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany
- Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology and Department of Internal Medicine III, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany
| | - Gene W Yeo
- Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
- Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Roman-Ulrich Müller
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany.
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
- Systems Biology of Ageing Cologne, University of Cologne, 50931, Cologne, Germany.
| | - Francesca Fabretti
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, 50937, Cologne, Germany
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27
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Shihabudeen Haider Ali MS, Cheng X, Moran M, Haemmig S, Naldrett MJ, Alvarez S, Feinberg MW, Sun X. LncRNA Meg3 protects endothelial function by regulating the DNA damage response. Nucleic Acids Res 2019; 47:1505-1522. [PMID: 30476192 PMCID: PMC6379667 DOI: 10.1093/nar/gky1190] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 11/05/2018] [Accepted: 11/09/2018] [Indexed: 01/10/2023] Open
Abstract
The role of long non-coding RNAs (lncRNAs) in regulating endothelial function through the DNA damage response (DDR) remains poorly understood. In this study, we demonstrate that lncRNA maternally expressed gene 3 (Meg3) interacts with the RNA binding protein polypyrimidine tract binding protein 3 (PTBP3) to regulate gene expression and endothelial function through p53 signaling ─ a major coordinator of apoptosis and cell proliferation triggered by the DDR. Meg3 expression is induced in endothelial cells (ECs) upon p53 activation. Meg3 silencing induces DNA damage, activates p53 signaling, increases the expression of p53 target genes, promotes EC apoptosis, and inhibits EC proliferation. Mechanistically, Meg3 silencing reduces the interaction of p53 with Mdm2, induces p53 expression, and promotes the association of p53 with the promoters of a subset of p53 target genes. PTBP3 silencing recapitulates the effects of Meg3 deficiency on the expression of p53 target genes, EC apoptosis and proliferation. The Meg3-dependent association of PTBP3 with the promoters of p53 target genes suggests that Meg3 and PTBP3 restrain p53 activation. Our studies reveal a novel role of Meg3 and PTBP3 in regulating p53 signaling and endothelial function, which may serve as novel targets for therapies to restore endothelial homeostasis.
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Affiliation(s)
| | - Xiao Cheng
- Department of Biochemistry, University of Nebraska-Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
| | - Matthew Moran
- Department of Biochemistry, University of Nebraska-Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
| | - Stefan Haemmig
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael J Naldrett
- Proteomics and Metabolomics Facility, Center for Biotechnology, University of Nebraska-Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
| | - Sophie Alvarez
- Proteomics and Metabolomics Facility, Center for Biotechnology, University of Nebraska-Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
| | - Mark W Feinberg
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xinghui Sun
- Department of Biochemistry, University of Nebraska-Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
- Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
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28
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Jo EB, Hong D, Lee YS, Lee H, Park JB, Kim SJ. Establishment of a Novel PDX Mouse Model and Evaluation of the Tumor Suppression Efficacy of Bortezomib Against Liposarcoma. Transl Oncol 2018; 12:269-281. [PMID: 30447641 PMCID: PMC6260470 DOI: 10.1016/j.tranon.2018.09.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 09/24/2018] [Accepted: 09/25/2018] [Indexed: 01/05/2023] Open
Abstract
The patient-derived xenograft (PDX) model has been adopted as a major tool for studying tumorigenesis and differentiation in various carcinomas. In addition, it has been used in the development of anticancer agents. PDX models have been among the most meaningful tools used to understand the role of stromal cells and vascular cells in the body, which are major factors in cancer development and the application of therapeutic agents. Also, the establishment of PDX models from liposarcoma patients is considered to be important for understanding lipomagenesis and following drugs development. For these reasons, we developed patient-derived cell (PDC) and PDX models derived from 20 liposarcoma patients. The tissues of these patients were obtained in accordance with the principles of the Samsung Medical Center's ethics policy, and cell culture and xenografting onto the mice were performed under these principles. High-throughput drug screening (HTS) was carried out using established PDCs to select candidate drugs. Among the different candidate anticancer drugs, we tested the effect of bortezomib, which was expected to inhibit MDM2 amplification. First, we confirmed that the PDCs maintained the characteristics of liposarcoma cells by assessing MDM2 amplification and CDK4 overexpression using fluorescence in situ hybridization. Analysis of short tandem repeats and an array using comparative genomic hybridization confirmed that the PDX model exhibited the same genomic profile as that of the patient. Immunohistochemistry for MDM2 and CDK4 showed that the overexpression patterns of both proteins were similar in the PDX models and the PDCs. Specifically, MDM2 amplification was observed to be significantly correlated with the successful establishment of PDX mouse models. However, CDK4 expression did not show such a correlation. Of the anticancer drugs selected through HTS, bortezomib showed a strong anticancer effect against PDC. In addition, we observed that bortezomib suppressed MDM2 expression in a dose-dependent manner. In contrast, p21 tended to elicit an increase in PDC expression. Treatment of the PDX model with bortezomib resulted in an anticancer effect similar to that seen in the PDCs. These results support that PDCs and PDX models are among the most powerful tools for the development and clinical application of anticancer drugs for the treatment of liposarcoma patients.
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Affiliation(s)
- Eun Byeol Jo
- Department of Health Sciences & Technology, Graduate School, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul; Transplantation Research Center, Samsung Biomedical Research Institute, Seoul, Republic of Korea
| | - Doopyo Hong
- Department of Health Sciences & Technology, Graduate School, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul
| | - Young Sang Lee
- Department of Health Sciences & Technology, Graduate School, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul; Transplantation Research Center, Samsung Biomedical Research Institute, Seoul, Republic of Korea
| | - Hyunjoo Lee
- Transplantation Research Center, Samsung Biomedical Research Institute, Seoul, Republic of Korea
| | - Jae Berm Park
- Department of Health Sciences & Technology, Graduate School, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul; Transplantation Research Center, Samsung Biomedical Research Institute, Seoul, Republic of Korea; Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung Joo Kim
- Department of Health Sciences & Technology, Graduate School, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul; Transplantation Research Center, Samsung Biomedical Research Institute, Seoul, Republic of Korea; Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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29
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Molavi G, Samadi N, Hosseingholi EZ. The roles of moonlight ribosomal proteins in the development of human cancers. J Cell Physiol 2018; 234:8327-8341. [PMID: 30417503 DOI: 10.1002/jcp.27722] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 09/23/2018] [Indexed: 12/13/2022]
Abstract
"Moonlighting protein" is a term used to define a single protein with multiple functions and different activities that are not derived from gene fusions, multiple RNA splicing, or the proteolytic activity of promiscuous enzymes. Different proteinous constituents of ribosomes have been shown to have important moonlighting extra-ribosomal functions. In this review, we introduce the impact of key moonlight ribosomal proteins and dependent signal transduction in the initiation and progression of various cancers. As a future perspective, the potential role of these moonlight ribosomal proteins in the diagnosis, prognosis, and development of novel strategies to improve the efficacy of therapies for human cancers has been suggested.
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Affiliation(s)
- Ghader Molavi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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30
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Dhuppar S, Mazumder A. Measuring cell cycle-dependent DNA damage responses and p53 regulation on a cell-by-cell basis from image analysis. Cell Cycle 2018; 17:1358-1371. [PMID: 29963960 DOI: 10.1080/15384101.2018.1482136] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
DNA damage in cells occurs from both endogenous and exogenous sources, and failure to repair such damage is associated with the emergence of different cancers, neurological disorders and aging. DNA damage responses (DDR) in cells are closely associated with the cell cycle. While most of our knowledge of DDR comes from bulk biochemistry, such methods require cells to be arrested at specific stages for cell cycle studies, potentially altering measured responses; nor is cell to cell variability in DDR or direct cell-level correlation of two response metrics measured in such methods. To overcome these limitations we developed a microscopy-based assay for determining cell cycle stages over large cell numbers. This method can be used to study cell-cycle-dependent DDR in cultured cells without the need for cell synchronization. Upon DNA damage γH2A.X induction was correlated to nuclear enrichment of p53 on a cell-by-cell basis and in a cell cycle dependent manner. Imaging-based cell cycle staging was combined with single molecule P53 mRNA detection and immunofluorescence for p53 protein in the very same cells to reveal an intriguing repression of P53 transcript numbers due to reduced transcription across different stages of the cell cycle during DNA damage. Our study hints at an unexplored mechanism for p53 regulation and underscores the importance of measuring single cell level responses to DNA damage.
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Affiliation(s)
- Shivnarayan Dhuppar
- a TIFR Centre for Interdisciplinary Sciences , TIFR Hyderabad , Hyderabad , India
| | - Aprotim Mazumder
- a TIFR Centre for Interdisciplinary Sciences , TIFR Hyderabad , Hyderabad , India
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31
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Ba Q, Li X, Huang C, Li J, Fu Y, Chen P, Duan J, Hao M, Zhang Y, Li J, Sun C, Ying H, Song H, Zhang R, Shen Z, Wang H. BCCIPβ modulates the ribosomal and extraribosomal function of S7 through a direct interaction. J Mol Cell Biol 2018; 9:209-219. [PMID: 28510697 PMCID: PMC5907838 DOI: 10.1093/jmcb/mjx019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Accepted: 05/14/2017] [Indexed: 11/14/2022] Open
Abstract
Extraribosomal functions of ribosomal proteins (RPs) have gained much attention for their implications in tumorigenesis and progression. However, the regulations for transition between the ribosomal and extraribosomal functions of RPs are rarely reported. Herein, we identified a ribosomal protein S7-interacting partner, BCCIPβ, which modulates the functional conversion of S7. Through the N-terminal acidic domain, BCCIPβ interacts with the central basic region in S7 and regulates the extraribosomal distribution of S7. BCCIPβ deficiency abrogates the ribosomal accumulation but enhances the ribosome-free location of S7. This translocation further impairs protein synthesis and triggers ribosomal stress. Consequently, BCCIPβ deficiency suppresses the ribosomal function and initiates the extraribosomal function of S7, resulting in restriction of cell proliferation. Moreover, clinically relevant S7 mutations were found to dampen the interaction with BCCIPβ and facilitate the functional transition of S7. In conclusion, BCCIPβ, as a S7 modulator, contributes to the regulation of ribosomal and extraribosomal functions of S7 and has implications in cell growth and tumor development.
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Affiliation(s)
- Qian Ba
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiaoguang Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chao Huang
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Junyang Li
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yijing Fu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Peizhan Chen
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Juan Duan
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Miao Hao
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yinghua Zhang
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jingquan Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chuanqi Sun
- Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Hao Ying
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Haiyun Song
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Ruiwen Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Zhiyuan Shen
- Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology of Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA
| | - Hui Wang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Correspondence to: Hui Wang, E-mail:
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32
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Wawrzynow B, Zylicz A, Zylicz M. Chaperoning the guardian of the genome. The two-faced role of molecular chaperones in p53 tumor suppressor action. Biochim Biophys Acta Rev Cancer 2018; 1869:161-174. [DOI: 10.1016/j.bbcan.2017.12.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 12/28/2017] [Accepted: 12/29/2017] [Indexed: 12/17/2022]
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33
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Katz C, Low-Calle AM, Choe JH, Laptenko O, Tong D, Joseph-Chowdhury JSN, Garofalo F, Zhu Y, Friedler A, Prives C. Wild-type and cancer-related p53 proteins are preferentially degraded by MDM2 as dimers rather than tetramers. Genes Dev 2018; 32:430-447. [PMID: 29549180 PMCID: PMC5900715 DOI: 10.1101/gad.304071.117] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 02/16/2018] [Indexed: 12/26/2022]
Abstract
The p53 tumor suppressor protein is the most well studied as a regulator of transcription in the nucleus, where it exists primarily as a tetramer. However, there are other oligomeric states of p53 that are relevant to its regulation and activities. In unstressed cells, p53 is normally held in check by MDM2 that targets p53 for transcriptional repression, proteasomal degradation, and cytoplasmic localization. Here we discovered a hydrophobic region within the MDM2 N-terminal domain that binds exclusively to the dimeric form of the p53 C-terminal domain in vitro. In cell-based assays, MDM2 exhibits superior binding to, hyperdegradation of, and increased nuclear exclusion of dimeric p53 when compared with tetrameric wild-type p53. Correspondingly, impairing the hydrophobicity of the newly identified N-terminal MDM2 region leads to p53 stabilization. Interestingly, we found that dimeric mutant p53 is partially unfolded and is a target for ubiquitin-independent degradation by the 20S proteasome. Finally, forcing certain tumor-derived mutant forms of p53 into dimer configuration results in hyperdegradation of mutant p53 and inhibition of p53-mediated cancer cell migration. Gaining insight into different oligomeric forms of p53 may provide novel approaches to cancer therapy.
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Affiliation(s)
- Chen Katz
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
| | - Ana Maria Low-Calle
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
| | - Joshua H Choe
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
| | - Oleg Laptenko
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
| | - David Tong
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
| | | | - Francesca Garofalo
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
| | | | - Assaf Friedler
- Institute of Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 9190401, Israel
| | - Carol Prives
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
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34
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Zhang M, Zhang J, Yan W, Chen X. p73 expression is regulated by ribosomal protein RPL26 through mRNA translation and protein stability. Oncotarget 2018; 7:78255-78268. [PMID: 27825141 PMCID: PMC5346636 DOI: 10.18632/oncotarget.13126] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 10/15/2016] [Indexed: 12/20/2022] Open
Abstract
p73, a p53 family tumor suppressor, is regulated by multiple mechanisms, including transcription and mRNA and protein stability. However, whether p73 expression is regulated via mRNA translation has not been explored. To test this, we examined whether ribosomal protein 26 (RPL26) plays a role in p73 expression. Here, we showed that p73 expression is controlled by RPL26 via protein stability and mRNA translation. To examine whether MDM2 mediates RPL26 to regulate p73 protein stability, we generated multiple MDM2-knockout cell lines by CRISPR-cas9. We found that in the absence of MDM2, the half-life of p73 protein is markedly increased. Interestingly, we also found that RPL26 is still capable of regulating p73 expression, albeit to a lesser extent, in MDM2-KO cells compared to that in isogenic control cells, suggesting that RPL26 regulates p73 expression via multiple mechanisms. Indeed, we found that RPL26 is necessary for efficient assembly of polysomes on p73 mRNA and de novo synthesis of p73 protein. Consistently, we found that RPL26 directly binds to p73 3′ untranslated region (3′UTR) and that RPL26 is necessary for efficient expression of an eGFP reporter that carries p73 3′UTR. We also found that RPL26 interacts with cap-binding protein eIF4E and enhances the association of eIF4E with p73 mRNA, leading to increased p73 mRNA translation. Finally, we showed that knockdown of RPL26 promotes, whereas ectopic expression of RPL26 inhibits, cell growth in a TAp73-dependent manner. Together, our data indicate that RPL26 regulates p73 expression via two distinct mechanisms: protein stability and mRNA translation.
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Affiliation(s)
- Min Zhang
- College of Life Sciences and Technology, Huazhong Agricultural University, Wuhan, China.,Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, CA, USA
| | - Jin Zhang
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, CA, USA
| | - Wensheng Yan
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, CA, USA
| | - Xinbin Chen
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, CA, USA
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35
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Zhao Y, Tan M, Liu X, Xiong X, Sun Y. Inactivation of ribosomal protein S27-like confers radiosensitivity via the Mdm2-p53 and Mdm2-MRN-ATM axes. Cell Death Dis 2018; 9:145. [PMID: 29396424 PMCID: PMC5833388 DOI: 10.1038/s41419-017-0192-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Revised: 11/27/2017] [Accepted: 11/28/2017] [Indexed: 01/21/2023]
Abstract
RPS27L (ribosomal protein S27-like) is an evolutionarily conserved ribosomal protein and a direct p53 target. We recently reported that Rps27l disruption triggers ribosomal stress to induce p53, causing postnatal death, which can be rescued by Trp53+/−. Whether and how Rps27l modulates radiosensitivity is unknown. Here we report that Rps27l−/−; Trp53+/− mice are extremely sensitive to radiation due to reduced proliferation and massive induction of apoptosis in radiation-sensitive organs. Mechanistically, the radiation sensitivity is mediated by two signaling pathways: (1) activated p53 pathway due to imbalanced Mdm2/Mdm4 levels and reduced E3 ligase activity; and (2) reduced DNA damage response due to reduced MRN/Atm signal as a result of elevated Mdm2 binding of Nbs1 to inhibit Nbs1–Atm binding and subsequent Atm activation. Indeed, heterozygous deletion of Mdm2 restores the MRN/Atm signal. Collectively, our study revealed a physiological condition under which Rps27l regulates the Mdm2/p53 and MRN/Atm axes to maintain DNA damage response and to confer radioprotection in vivo.
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Affiliation(s)
- Yongchao Zhao
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. .,Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. .,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Mingjia Tan
- Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
| | - Xia Liu
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiufang Xiong
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. .,Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
| | - Yi Sun
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. .,Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. .,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
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36
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Sulima SO, Hofman IJF, De Keersmaecker K, Dinman JD. How Ribosomes Translate Cancer. Cancer Discov 2017; 7:1069-1087. [PMID: 28923911 PMCID: PMC5630089 DOI: 10.1158/2159-8290.cd-17-0550] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 07/18/2017] [Accepted: 07/31/2017] [Indexed: 12/13/2022]
Abstract
A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here, we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis-from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on "onco-ribosomes" as an Achilles' heel of cancer cells and a promising target for further therapeutic intervention.Significance: The recent discovery of somatic mutations in ribosomal proteins in several cancers has strengthened the link between ribosome defects and cancer progression, while also raising the question of which cellular mechanisms such defects exploit. Here, we discuss the emerging molecular mechanisms by which ribosomes support oncogenesis, and how this understanding is driving the design of novel therapeutic strategies. Cancer Discov; 7(10); 1069-87. ©2017 AACR.
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Affiliation(s)
- Sergey O Sulima
- Department of Oncology, KU Leuven, University of Leuven, LKI, Leuven Cancer Institute, Leuven, Belgium
| | - Isabel J F Hofman
- Department of Oncology, KU Leuven, University of Leuven, LKI, Leuven Cancer Institute, Leuven, Belgium
| | - Kim De Keersmaecker
- Department of Oncology, KU Leuven, University of Leuven, LKI, Leuven Cancer Institute, Leuven, Belgium.
| | - Jonathan D Dinman
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland.
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37
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Takafuji T, Kayama K, Sugimoto N, Fujita M. GRWD1, a new player among oncogenesis-related ribosomal/nucleolar proteins. Cell Cycle 2017; 16:1397-1403. [PMID: 28722511 DOI: 10.1080/15384101.2017.1338987] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Increasing attention has been paid to certain ribosomal or ribosome biosynthesis-related proteins involved in oncogenesis. Members of one group are classified as "tumor suppressive factors" represented by RPL5 and RPL11; loss of their functions leads to cancer predisposition. RPL5 and RPL11 prevent tumorigenesis by binding to and inhibiting the MDM2 ubiquitin ligase and thereby up-regulating p53. Many other candidate tumor suppressive ribosomal/nucleolar proteins have been suggested. However, it remains to be experimentally clarified whether many of these factors can actually prevent tumorigenesis and if so, how they do so. Conversely, some ribosomal/nucleolar proteins promote tumorigenesis. For example, PICT1 binds to and anchors RPL11 in nucleoli, down-regulating p53 and promoting tumorigenesis. GRWD1 was recently identified as another such factor. When overexpressed, GRWD1 suppresses p53 and transforms normal human cells, probably by binding to RPL11 and sequestrating it from MDM2. However, other pathways may also be involved.
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Affiliation(s)
- Takuya Takafuji
- a Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences , Kyushu University , Higashi-ku, Fukuoka , Japan
| | - Kota Kayama
- a Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences , Kyushu University , Higashi-ku, Fukuoka , Japan
| | - Nozomi Sugimoto
- a Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences , Kyushu University , Higashi-ku, Fukuoka , Japan
| | - Masatoshi Fujita
- a Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences , Kyushu University , Higashi-ku, Fukuoka , Japan
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38
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HIV-1 Tat potently stabilises Mdm2 and enhances viral replication. Biochem J 2017; 474:2449-2464. [PMID: 28468838 PMCID: PMC5509382 DOI: 10.1042/bcj20160825] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 04/23/2017] [Accepted: 05/02/2017] [Indexed: 12/31/2022]
Abstract
Murine double minute 2 (Mdm2) is known to enhance the transactivation potential of human immunodeficiency virus (HIV-1) Tat protein by causing its ubiquitination. However, the regulation of Mdm2 during HIV-1 infection and its implications for viral replication have not been well studied. Here, we show that the Mdm2 protein level increases during HIV-1 infection and this effect is mediated by HIV-1 Tat protein. Tat appears to stabilise Mdm2 at the post-translational level by inducing its phosphorylation at serine-166 position through AKT. Although p53 is one of the key players for Mdm2 induction, Tat-mediated stabilisation of Mdm2 appears to be independent of p53. Moreover, the non-phosphorylatable mutant of Mdm2 (S166A) fails to interact with Tat and shows decreased half-life in the presence of Tat compared with wild-type Mdm2. Furthermore, the non-phosphorylatable mutant of Mdm2 (S166A) is unable to support HIV-1 replication. Thus, HIV-1 Tat appears to stabilise Mdm2, which in turn enhances Tat-mediated viral replication. This study highlights the importance of post-translational modifications of host cellular factors in HIV-1 replication and pathogenesis.
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39
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Systematic approaches to identify E3 ligase substrates. Biochem J 2017; 473:4083-4101. [PMID: 27834739 PMCID: PMC5103871 DOI: 10.1042/bcj20160719] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Revised: 08/25/2016] [Accepted: 08/30/2016] [Indexed: 12/11/2022]
Abstract
Protein ubiquitylation is a widespread post-translational modification, regulating cellular signalling with many outcomes, such as protein degradation, endocytosis, cell cycle progression, DNA repair and transcription. E3 ligases are a critical component of the ubiquitin proteasome system (UPS), determining the substrate specificity of the cascade by the covalent attachment of ubiquitin to substrate proteins. Currently, there are over 600 putative E3 ligases, but many are poorly characterized, particularly with respect to individual protein substrates. Here, we highlight systematic approaches to identify and validate UPS targets and discuss how they are underpinning rapid advances in our understanding of the biochemistry and biology of the UPS. The integration of novel tools, model systems and methods for target identification is driving significant interest in drug development, targeting various aspects of UPS function and advancing the understanding of a diverse range of disease processes.
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40
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Chen J, Crutchley J, Zhang D, Owzar K, Kastan MB. Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers. Cancer Discov 2017; 7:766-781. [PMID: 28288992 DOI: 10.1158/2159-8290.cd-16-0908] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 10/14/2016] [Accepted: 03/09/2017] [Indexed: 01/10/2023]
Abstract
Cellular responses to DNA damage are critical determinants of cancer development and aging-associated pathogenesis. Here, we identify and characterize a DNA-damage response (DDR) pathway that regulates alternative splicing of numerous gene products, including the human tumor suppressor TP53, and controls DNA damage-induced cellular senescence. In brief, ionizing radiation (IR) inhibits the activity of SMG1, a phosphoinositide-3-kinase-like kinase family member, reducing the binding of SMG1 to a specific region near exon 9 of p53 precursor mRNA and promoting the binding of ribosomal protein L26 (RPL26) to p53 pre-mRNA. RPL26, in turn, is required for the recruitment of the serine/arginine-rich splicing factor SRSF7 to p53 pre-mRNA and generation of alternatively spliced p53β RNA. Disruption of this pathway via selective knockout of p53β by CRISPR/Cas9 or downregulation of pathway constituents significantly reduces IR-induced senescence markers, and cells lacking p53β expression fail to transcriptionally repress negative regulators of cellular senescence and aging.Significance: We identified a new component of the DDR pathway that regulates alternative splicing of messenger RNAs, including human TP53 mRNA. Modulation of this regulatory pathway affects DNA-damage induction of cellular senescence markers. Cancer Discov; 7(7); 766-81. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.
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Affiliation(s)
- Jing Chen
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.,Duke Cancer Institute, Duke University, Durham, North Carolina
| | - John Crutchley
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.,Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Dadong Zhang
- Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Kouros Owzar
- Duke Cancer Institute, Duke University, Durham, North Carolina.,Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
| | - Michael B Kastan
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina. .,Duke Cancer Institute, Duke University, Durham, North Carolina
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41
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Zhou X, Cao B, Lu H. Negative auto-regulators trap p53 in their web. J Mol Cell Biol 2017; 9:62-68. [PMID: 28069666 PMCID: PMC5907828 DOI: 10.1093/jmcb/mjx001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/14/2016] [Accepted: 01/06/2017] [Indexed: 01/07/2023] Open
Abstract
The transcriptional factor p53 activates the expression of a myriad of target genes involving a complicated signalling network, resulting in various cellular outcomes, such as growth arrest, senescence, apoptosis, and metabolic changes, and leading to consequent suppression of tumour growth and progression. Because of the profoundly adverse effect of p53 on growth and proliferation of cancer cells, several feedback mechanisms have been employed by the cells to constrain p53 activity. Two major antagonists MDM2 and MDMX (the long forms) are transcriptionally induced by p53, but in return block p53 activity, forming a negative feedback circuit and rendering chemoresistance of several cancer cells. However, they are not alone, as cancer cells also employ other proteins encoded by p53 target genes to inhibit p53 activity at transcriptional, translational, and posttranslational levels. This essay is thus composed to review a recent progress in understanding the mechanisms for how cancer cells hijack the p53 autoregulation by these proteins for their growth advantage and to discuss the clinical implications of these autoregulatory loops.
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Affiliation(s)
- Xiang Zhou
- Fudan University Shanghai Cancer Center and the Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Bo Cao
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Hua Lu
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
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42
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Ribosomal Proteins Control or Bypass p53 during Nucleolar Stress. Int J Mol Sci 2017; 18:ijms18010140. [PMID: 28085118 PMCID: PMC5297773 DOI: 10.3390/ijms18010140] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/12/2016] [Accepted: 01/05/2017] [Indexed: 12/20/2022] Open
Abstract
The nucleolus is the site of ribosome biogenesis, a complex process that requires the coordinate activity of all three RNA polymerases and hundreds of non-ribosomal factors that participate in the maturation of ribosomal RNA (rRNA) and assembly of small and large subunits. Nevertheless, emerging studies have highlighted the fundamental role of the nucleolus in sensing a variety of cellular stress stimuli that target ribosome biogenesis. This condition is known as nucleolar stress and triggers several response pathways to maintain cell homeostasis, either p53-dependent or p53-independent. The mouse double minute (MDM2)-p53 stress signaling pathways are activated by multiple signals and are among the most important regulators of cellular homeostasis. In this review, we will focus on the role of ribosomal proteins in p53-dependent and p53-independent response to nucleolar stress considering novel identified regulators of these pathways. We describe, in particular, the role of ribosomal protein uL3 (rpL3) in p53-independent nucleolar stress signaling pathways.
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43
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Fahl SP, Wang M, Zhang Y, Duc ACE, Wiest DL. Regulatory Roles of Rpl22 in Hematopoiesis: An Old Dog with New Tricks. Crit Rev Immunol 2016; 35:379-400. [PMID: 26853850 DOI: 10.1615/critrevimmunol.v35.i5.30] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Ribosomal proteins have long been known to serve critical roles in facilitating the biogenesis of the ribosome and its ability to synthesize proteins. However, evidence is emerging that suggests ribosomal proteins are also capable of performing tissue-restricted, regulatory functions that impact normal development and pathological conditions, including cancer. The challenge in studying such regulatory functions is that elimination of many ribosomal proteins also disrupts ribosome biogenesis and/or function. Thus, it is difficult to determine whether developmental abnormalities resulting from ablation of a ribosomal protein result from loss of core ribosome functions or from loss of the regulatory function of the ribosomal protein. Rpl22, a ribosomal protein component of the large 60S subunit, provides insight into this conundrum; Rpl22 is dispensable for both ribosome biogenesis and protein synthesis yet its ablation causes tissue-restricted disruptions in development. Here we review evidence supporting the regulatory functions of Rpl22 and other ribosomal proteins.
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Affiliation(s)
- Shawn P Fahl
- Blood Cell Development and Function Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111
| | - Minshi Wang
- Blood Cell Development and Function Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111
| | - Yong Zhang
- Blood Cell Development and Function Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111
| | - Anne-Cecile E Duc
- Blood Cell Development and Function Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111
| | - David L Wiest
- Blood Cell Development and Function Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111
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44
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Mao Q, Zhang PH, Yang J, Xu JD, Kong M, Shen H, Zhu H, Bai M, Zhou L, Li GF, Wang Q, Li SL. iTRAQ-Based Proteomic Analysis of Ginsenoside F 2 on Human Gastric Carcinoma Cells SGC7901. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2016; 2016:2635483. [PMID: 27829861 PMCID: PMC5088344 DOI: 10.1155/2016/2635483] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 08/04/2016] [Accepted: 08/25/2016] [Indexed: 12/16/2022]
Abstract
Ginsenoside F2 (F2), a protopanaxdiol type of saponin, was reported to inhibit human gastric cancer cells SGC7901. To better understand the molecular mechanisms of F2, an iTRAQ-based proteomics approach was applied to define protein expression profiles in SGC7901 cells in response to lower dose (20 μM) and shorter duration (12 hour) of F2 treatment, compared with previous study. 205 proteins were screened in terms of the change in their expression level which met our predefined criteria. Further bioinformatics and experiments demonstrated that F2 treatment downregulated PRR5 and RPS15 and upregulated RPL26, which are implicated in ribosomal protein-p53 signaling pathway. F2 also inhibited CISD2, Bcl-xl, and NLRX1, which are associated with autophagic pathway. Furthermore, it was demonstrated that F2 treatment increased Atg5, Atg7, Atg10, and PUMA, the critical downstream effectors of ribosomal protein-p53 signaling pathway, and Beclin-1, UVRAG, and AMBRA-1, the important molecules in Bcl-xl/Beclin-1 pathway. The 6 differentially abundant proteins, PRR5, CISD2, Bcl-xl, NLRX1, RPS15, and RPL26, were confirmed by western blot. Taken together, ribosomal protein-p53 signaling pathway and Bcl-xl/Beclin-1 pathway might be the most significantly regulated biological process by F2 treatment in SGC7901 cells, which provided valuable insights into the deep understanding of the molecular mechanisms of F2 for gastric cancer treatment.
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Affiliation(s)
- Qian Mao
- Department of Pharmaceutical Analysis & Metabolomics, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Pin-Hu Zhang
- Jiangsu Center for New Drug Screening & National New Drug Screening Laboratory, China Pharmaceutical University, Nanjing 210009, China
| | - Jie Yang
- Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, China
| | - Jin-Di Xu
- Department of Pharmaceutical Analysis & Metabolomics, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Ming Kong
- Department of Pharmaceutical Analysis & Metabolomics, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Hong Shen
- Department of Pharmaceutical Analysis & Metabolomics, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - He Zhu
- Department of Pharmaceutical Analysis & Metabolomics, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Min Bai
- Department of Pharmaceutical Analysis & Metabolomics, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Li Zhou
- Department of Pharmaceutical Analysis & Metabolomics, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Guang-Fu Li
- Department of Surgery, The Medical University of South Carolina, Charleston, SC 29466, USA
| | - Qiang Wang
- Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, China
| | - Song-Lin Li
- Department of Pharmaceutical Analysis & Metabolomics, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
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45
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Allosteric Interactions by p53 mRNA Govern HDM2 E3 Ubiquitin Ligase Specificity under Different Conditions. Mol Cell Biol 2016; 36:2195-205. [PMID: 27215386 DOI: 10.1128/mcb.00113-16] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 05/20/2016] [Indexed: 11/20/2022] Open
Abstract
HDM2 and HDMX are key negative regulatory factors of the p53 tumor suppressor under normal conditions by promoting its degradation or preventing its trans activity, respectively. It has more recently been shown that both proteins can also act as positive regulators of p53 after DNA damage. This involves phosphorylation by ATM on serine residues HDM2(S395) and HDMX(S403), promoting their respective interaction with the p53 mRNA. However, the underlying molecular mechanisms of how these phosphorylation events switch HDM2 and HDMX from negative to positive regulators of p53 is not known. Our results show that these phosphorylation events reside within intrinsically disordered domains and change the conformation of the proteins. The modifications promote the exposition of N-terminal interfaces that support the formation of a new HDMX-HDM2 heterodimer independent of the C-terminal RING-RING interaction. The E3 ubiquitin ligase activity of this complex toward p53 is prevented by the p53 mRNA ligand but, interestingly, does not affect the capacity to ubiquitinate HDMX and HDM2. These results show how ATM-mediated modifications of HDMX and HDM2 switch HDM2 E3 ubiquitin ligase activity away from p53 but toward HDMX and itself and illustrate how the substrate specificity of HDM2 E3 ligase activity is regulated.
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46
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Xu X, Xiong X, Sun Y. The role of ribosomal proteins in the regulation of cell proliferation, tumorigenesis, and genomic integrity. SCIENCE CHINA-LIFE SCIENCES 2016; 59:656-72. [DOI: 10.1007/s11427-016-0018-0] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 04/06/2016] [Indexed: 01/29/2023]
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47
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Duan Y, Ma G, Huang X, D'Amore PA, Zhang F, Lei H. The Clustered, Regularly Interspaced, Short Palindromic Repeats-associated Endonuclease 9 (CRISPR/Cas9)-created MDM2 T309G Mutation Enhances Vitreous-induced Expression of MDM2 and Proliferation and Survival of Cells. J Biol Chem 2016; 291:16339-47. [PMID: 27246850 DOI: 10.1074/jbc.m116.729467] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Indexed: 01/09/2023] Open
Abstract
The G309 allele of SNPs in the mouse double minute (MDM2) promoter locus is associated with a higher risk of cancer and proliferative vitreoretinopathy (PVR), but whether SNP G309 contributes to the pathogenesis of PVR is to date unknown. The clustered regularly interspaced short palindromic repeats (CRISPR)-associated endonuclease (Cas) 9 from Streptococcus pyogenes (SpCas9) can be harnessed to manipulate a single or multiple nucleotides in mammalian cells. Here we delivered SpCas9 and guide RNAs using dual adeno-associated virus-derived vectors to target the MDM2 genomic locus together with a homologous repair template for creating the mutation of MDM2 T309G in human primary retinal pigment epithelial (hPRPE) cells whose genotype is MDM2 T309T. The next-generation sequencing results indicated that there was 42.51% MDM2 G309 in the edited hPRPE cells using adeno-associated viral CRISPR/Cas9. Our data showed that vitreous induced an increase in MDM2 and subsequent attenuation of p53 expression in MDM2 T309G hPRPE cells. Furthermore, our experimental results demonstrated that MDM2 T309G in hPRPE cells enhanced vitreous-induced cell proliferation and survival, suggesting that this SNP contributes to the pathogenesis of PVR.
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Affiliation(s)
- Yajian Duan
- From the Schepens Eye Research Institute, Massachusetts Eye and Ear, and Departments of Ophthalmology and the Shanxi Eye Hospital, Taiyuan, Shanxi 030000, China
| | - Gaoen Ma
- From the Schepens Eye Research Institute, Massachusetts Eye and Ear, and Departments of Ophthalmology and
| | - Xionggao Huang
- From the Schepens Eye Research Institute, Massachusetts Eye and Ear, and Departments of Ophthalmology and
| | - Patricia A D'Amore
- From the Schepens Eye Research Institute, Massachusetts Eye and Ear, and Departments of Ophthalmology and Pathology, Harvard Medical School, Boston, Massachusetts 02114
| | - Feng Zhang
- the Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, and
| | - Hetian Lei
- From the Schepens Eye Research Institute, Massachusetts Eye and Ear, and Departments of Ophthalmology and
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48
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Gizak A, Grenda M, Mamczur P, Wisniewski J, Sucharski F, Silberring J, McCubrey JA, Wisniewski JR, Rakus D. Insulin/IGF1-PI3K-dependent nucleolar localization of a glycolytic enzyme--phosphoglycerate mutase 2, is necessary for proper structure of nucleolus and RNA synthesis. Oncotarget 2016; 6:17237-50. [PMID: 26033454 PMCID: PMC4627304 DOI: 10.18632/oncotarget.4044] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 04/30/2015] [Indexed: 12/31/2022] Open
Abstract
Phosphoglycerate mutase (PGAM), a conserved, glycolytic enzyme has been found in nucleoli of cancer cells. Here, we present evidence that accumulation of PGAM in the nucleolus is a universal phenomenon concerning not only neoplastically transformed but also non-malignant cells. Nucleolar localization of the enzyme is dependent on the presence of the PGAM2 (muscle) subunit and is regulated by insulin/IGF-1–PI3K signaling pathway as well as drugs influencing ribosomal biogenesis. We document that PGAM interacts with several 40S and 60S ribosomal proteins and that silencing of PGAM2 expression results in disturbance of nucleolar structure, inhibition of RNA synthesis and decrease of the mitotic index of squamous cell carcinoma cells. We conclude that presence of PGAM in the nucleolus is a prerequisite for synthesis and initial assembly of new pre-ribosome subunits.
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Affiliation(s)
- Agnieszka Gizak
- Department of Animal Molecular Physiology, Wroclaw University, Cybulskiego, Wroclaw, Poland
| | - Marcin Grenda
- Department of Animal Molecular Physiology, Wroclaw University, Cybulskiego, Wroclaw, Poland
| | - Piotr Mamczur
- Department of Animal Molecular Physiology, Wroclaw University, Cybulskiego, Wroclaw, Poland
| | - Janusz Wisniewski
- Department of Animal Molecular Physiology, Wroclaw University, Cybulskiego, Wroclaw, Poland
| | - Filip Sucharski
- Department of Biochemistry and Neurobiology, Faculty of Materials Science and Ceramics, AGH University of Science and Technology, Kraków, Poland
| | - Jerzy Silberring
- Department of Biochemistry and Neurobiology, Faculty of Materials Science and Ceramics, AGH University of Science and Technology, Kraków, Poland
| | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Jacek R Wisniewski
- Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Martinsried, Germany
| | - Dariusz Rakus
- Department of Animal Molecular Physiology, Wroclaw University, Cybulskiego, Wroclaw, Poland
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49
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Huang L, Li J, Anboukaria H, Luo Z, Zhao M, Wu H. Comparative transcriptome analyses of seven anurans reveal functions and adaptations of amphibian skin. Sci Rep 2016; 6:24069. [PMID: 27040083 PMCID: PMC4819189 DOI: 10.1038/srep24069] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 03/18/2016] [Indexed: 01/06/2023] Open
Abstract
Animal skin, which is the tissue that directly contacts the external surroundings, has evolved diverse functions to adapt to various environments. Amphibians represent the transitional taxon from aquatic to terrestrial life. Exploring the molecular basis of their skin function and adaptation is important to understand the survival and evolutionary mechanisms of vertebrates. However, comprehensive studies on the molecular mechanisms of skin functions in amphibians are scarce. In this study, we sequenced the skin transcriptomes of seven anurans belonging to three families and compared the similarities and differences in expressed genes and proteins. Unigenes and pathways related to basic biological processes and special functions, such as defense, immunity, and respiration, were enriched in functional annotations. A total of 108 antimicrobial peptides were identified. The highly expressed genes were similar in species of the same family but were different among families. Additionally, the positively selected orthologous groups were involved in biosynthesis, metabolism, immunity, and defense processes. This study is the first to generate extensive transcriptome data for the skin of seven anurans and provides unigenes and pathway candidates for further studies on amphibian skin function and adaptation.
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Affiliation(s)
- Li Huang
- Institute of Evolution and Ecology, School of Life Sciences, Central China Normal University, 152 Luoyulu, Hongshan District, Wuhan 430079, China
| | - Jun Li
- Institute of Evolution and Ecology, School of Life Sciences, Central China Normal University, 152 Luoyulu, Hongshan District, Wuhan 430079, China
| | - Housseni Anboukaria
- Institute of Evolution and Ecology, School of Life Sciences, Central China Normal University, 152 Luoyulu, Hongshan District, Wuhan 430079, China
| | - Zhenhua Luo
- Institute of Evolution and Ecology, School of Life Sciences, Central China Normal University, 152 Luoyulu, Hongshan District, Wuhan 430079, China
| | - Mian Zhao
- Institute of Evolution and Ecology, School of Life Sciences, Central China Normal University, 152 Luoyulu, Hongshan District, Wuhan 430079, China
| | - Hua Wu
- Institute of Evolution and Ecology, School of Life Sciences, Central China Normal University, 152 Luoyulu, Hongshan District, Wuhan 430079, China
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50
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Liu Y, Deisenroth C, Zhang Y. RP-MDM2-p53 Pathway: Linking Ribosomal Biogenesis and Tumor Surveillance. Trends Cancer 2016; 2:191-204. [PMID: 28741571 DOI: 10.1016/j.trecan.2016.03.002] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Revised: 03/03/2016] [Accepted: 03/04/2016] [Indexed: 12/18/2022]
Abstract
Ribosomal biogenesis is tightly associated with cellular activities, such as growth, proliferation, and cell cycle progression. Perturbations in ribosomal biogenesis can initiate so-called nucleolar stress. The process through which ribosomal proteins (RPs) transduce nucleolar stress signals via MDM2 to p53 has been described as a crucial tumor-suppression mechanism. In this review we focus on recent progress pertaining to the function and mechanism of RPs in association with the MDM2-p53 tumor-suppression network, and the potential implications this surveillance network has for cancer development.
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Affiliation(s)
- Yong Liu
- Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Chad Deisenroth
- The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, 6 Davis Drive, PO Box 12137, Research Triangle Park, NC 27709, USA
| | - Yanping Zhang
- Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
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