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Mohammad Nezhady MA, Cagnone G, Bajon E, Chaudhari P, Modaresinejad M, Hardy P, Maggiorani D, Quiniou C, Joyal JS, Beauséjour C, Chemtob S. Unconventional receptor functions and location-biased signaling of the lactate GPCR in the nucleus. Life Sci Alliance 2025; 8:e202503226. [PMID: 39904567 PMCID: PMC11794946 DOI: 10.26508/lsa.202503226] [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: 01/15/2025] [Revised: 01/22/2025] [Accepted: 01/23/2025] [Indexed: 02/06/2025] Open
Abstract
G-protein-coupled receptors (GPCRs) are virtually involved in every physiological process. However, mechanisms for their ability to regulate a vast array of different processes remain elusive. An unconventional functional modality could at least in part account for such diverse involvements but has yet to be explored. We found HCAR1, a multifunctional lactate GPCR, to localize at the nucleus and therein capable of initiating location-biased signaling notably nuclear-ERK and AKT. We discovered that nuclear HCAR1 (N-HCAR1) is directly involved in regulating diverse processes. Specifically, N-HCAR1 binds to protein complexes that are involved in promoting protein translation, ribosomal biogenesis, and DNA-damage repair. N-HCAR1 also interacts with chromatin remodelers to directly regulate gene expression. We show that N-HCAR1 displays a broader transcriptomic signature than its plasma membrane counterpart. Interestingly, exclusion of HCAR1 from the nucleus has the same effect as its complete cellular depletion on tumor growth and metastasis in vivo. These results reveal noncanonical functions for a cell nucleus-localized GPCR that are distinct from traditional receptor modalities and through which HCAR1 can participate in regulating various cellular processes.
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Affiliation(s)
- Mohammad Ali Mohammad Nezhady
- https://ror.org/0161xgx34 Program in Molecular Biology, Faculty of Medicine, Université de Montréal, Montreal, Canada
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
| | - Gael Cagnone
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
| | - Emmanuel Bajon
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
| | - Prabhas Chaudhari
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
- Department of Experimental Medicine, McGill University, Montréal, Canada
| | - Monir Modaresinejad
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
- https://ror.org/0161xgx34 Program in Biomedical Sciences, Faculty of Medicine, Université de Montréal, Montreal, Canada
| | - Pierre Hardy
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
| | - Damien Maggiorani
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
- https://ror.org/0161xgx34 Department of Pharmacology, Université de Montréal, Montreal, Canada
| | - Christiane Quiniou
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
| | - Jean-Sébastien Joyal
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
- https://ror.org/0161xgx34 Department of Pharmacology, Université de Montréal, Montreal, Canada
| | - Christian Beauséjour
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
| | - Sylvain Chemtob
- https://ror.org/0161xgx34 Program in Molecular Biology, Faculty of Medicine, Université de Montréal, Montreal, Canada
- https://ror.org/01gv74p78 Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada
- https://ror.org/0161xgx34 Department of Pharmacology, Université de Montréal, Montreal, Canada
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Brzezinski M, Argudo PG, Scheidt T, Yu M, Hosseini E, Kaltbeitzel A, Lemke EA, Michels JJ, Parekh SH. Protein-Specific Crowding Accelerates Aging in Protein Condensates. Biomacromolecules 2024. [PMID: 39648588 DOI: 10.1021/acs.biomac.4c00609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/10/2024]
Abstract
Macromolecular crowding agents, such as poly(ethylene glycol) (PEG), are often used to mimic cellular cytoplasm in protein assembly studies. Despite the perception that crowding agents have an inert nature, we demonstrate and quantitatively explore the diverse effects of PEG on the phase separation and maturation of protein condensates. We use two model proteins, the FG domain of Nup98 and bovine serum albumin (BSA), which represent an intrinsically disordered protein and a protein with a well-established secondary structure, respectively. PEG expedites the maturation of Nup98, enhancing denser protein packing and fortifying interactions, which hasten beta-sheet formation and subsequent droplet gelation. In contrast to BSA, PEG enhances droplet stability and limits the available solvent for protein solubilization, inducing only minimal changes in the secondary structure, pointing toward a significantly different role of the crowding agent. Strikingly, we detect almost no presence of PEG in Nup droplets, whereas PEG is moderately detectable within BSA droplets. Our findings demonstrate a nuanced interplay between crowding agents and proteins; PEG can accelerate protein maturation in liquid-liquid phase separation systems, but its partitioning and effect on protein structure in droplets is protein specific. This suggests that crowding phenomena are specific to each protein-crowding agent pair.
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Affiliation(s)
- Mateusz Brzezinski
- Department of Biomedical Engineering University of Texas at Austin, 107 W. Dean Keeton Rd., Austin, Texas 78712, United States
- Max Planck Institute for Polymer Research Ackermannweg 10, Mainz 55128, Germany
| | - Pablo G Argudo
- Max Planck Institute for Polymer Research Ackermannweg 10, Mainz 55128, Germany
| | - Tom Scheidt
- Biocenter, Johannes Gutenberg University Mainz, Hanns-Dieter-Hüsch-Weg 17, Mainz 55128, Germany
- Institute of Molecular Biology GmbH, Ackermannweg 4, Mainz 55128, Germany
| | - Miao Yu
- Biocenter, Johannes Gutenberg University Mainz, Hanns-Dieter-Hüsch-Weg 17, Mainz 55128, Germany
- Institute of Molecular Biology GmbH, Ackermannweg 4, Mainz 55128, Germany
| | - Elnaz Hosseini
- Department of Biomedical Engineering University of Texas at Austin, 107 W. Dean Keeton Rd., Austin, Texas 78712, United States
- Max Planck Institute for Polymer Research Ackermannweg 10, Mainz 55128, Germany
| | - Anke Kaltbeitzel
- Max Planck Institute for Polymer Research Ackermannweg 10, Mainz 55128, Germany
| | - Edward A Lemke
- Biocenter, Johannes Gutenberg University Mainz, Hanns-Dieter-Hüsch-Weg 17, Mainz 55128, Germany
- Institute of Molecular Biology GmbH, Ackermannweg 4, Mainz 55128, Germany
| | - Jasper J Michels
- Max Planck Institute for Polymer Research Ackermannweg 10, Mainz 55128, Germany
| | - Sapun H Parekh
- Department of Biomedical Engineering University of Texas at Austin, 107 W. Dean Keeton Rd., Austin, Texas 78712, United States
- Max Planck Institute for Polymer Research Ackermannweg 10, Mainz 55128, Germany
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Dhiman S, Dhillon V, Balasubramanian SK. Targeting Menin in Acute Myeloid Leukemia: Therapeutic Advances and Future Directions. Cancers (Basel) 2024; 16:3743. [PMID: 39594699 PMCID: PMC11592310 DOI: 10.3390/cancers16223743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/31/2024] [Accepted: 10/31/2024] [Indexed: 11/28/2024] Open
Abstract
Germline mutations in the MEN1 gene encoding menin protein cause multiple endocrine neoplasia type 1 (MEN1) syndrome. Recent evidence suggests that inhibiting the interaction of menin with its crucial oncogenic protein partners represents a promising therapeutic strategy to AML. Menin plays a critical role in lysine methyltransferase 2A (KMT2A)-gene-rearranged and NPM1-m acute leukemias, both associated with adverse outcomes with current standard therapies, especially in the relapsed/refractory setting. Disrupting the menin-KMT2A interaction affects the proleukemogenic HOX/MEIS transcription program. This disruption leads to the differentiation of KMT2Ar and NPM1-m AML cells. Small molecular inhibitors of the menin-KMT2A interaction target the central cavity of MEN1 to inhibit the MEN1-KMT2A interaction and could target a similar transcriptional dependency in other leukemia subsets, broadening their therapeutic potential. These agents, both as monotherapies and in combination with synergistic drugs, are undergoing preclinical and clinical evaluation with promising early results. With the growing literature around menin inhibitors in AML, we discussed the biology of menin, its mechanism of action, its interacting partners in leukemia, possible inhibitors, their implications, synergistic drugs, and future therapeutic strategies in this review.
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Affiliation(s)
- Sandhya Dhiman
- Department of Oncology, Karmanos Cancer Center, School of Medicine, Wayne State University, Detroit, MI 48201, USA; (S.D.); (V.D.)
| | - Vikram Dhillon
- Department of Oncology, Karmanos Cancer Center, School of Medicine, Wayne State University, Detroit, MI 48201, USA; (S.D.); (V.D.)
- Department of Oncology, Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Suresh Kumar Balasubramanian
- Department of Oncology, Karmanos Cancer Center, School of Medicine, Wayne State University, Detroit, MI 48201, USA; (S.D.); (V.D.)
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Pereira RT, Samarakone C, Bridger JM, de Castro IJ. Pushing the envelope - How the genome interacts with the nuclear envelope in health and disease. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 143:155-190. [PMID: 39843135 DOI: 10.1016/bs.apcsb.2024.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
The nuclear envelope has for long been considered more than just the physical border between the nucleoplasm and the cytoplasm, emerging as a crucial player in genome organisation and regulation within the 3D nucleus. Consequently, its study has become a valuable topic in the research of cancer, ageing and several other diseases where chromatin organisation is compromised. In this chapter, we will delve into its several sub-elements, such as the nuclear lamina, nuclear pore complexes and nuclear envelope proteins, and their diverse roles in nuclear function and maintenance. We will explore their functions beyond nuclear structure and transport focusing on their interactions with chromatin and their paramount influence in its organisation, regulation and expression at the nuclear periphery. Finally, we will outline how this chromatin organisation and regulation at the nuclear envelope is affected in diseases, including laminopathies, cancer, neurodegenerative diseases and during viral infections.
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Affiliation(s)
- Rita Torres Pereira
- Genome Organisation and Dynamics Cluster, Center for Genome Engineering and Maintenance, Division of Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, London, United Kingdom
| | - Cresentia Samarakone
- Genome Organisation and Dynamics Cluster, Center for Genome Engineering and Maintenance, Division of Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, London, United Kingdom
| | - Joanna M Bridger
- Genome Organisation and Dynamics Cluster, Center for Genome Engineering and Maintenance, Division of Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, London, United Kingdom
| | - Ines J de Castro
- Genome Organisation and Dynamics Cluster, Center for Genome Engineering and Maintenance, Division of Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, London, United Kingdom.
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Chen S, Jiang Q, Fan J, Cheng H. Nuclear mRNA export. Acta Biochim Biophys Sin (Shanghai) 2024; 57:84-100. [PMID: 39243141 PMCID: PMC11802349 DOI: 10.3724/abbs.2024145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 07/17/2024] [Indexed: 09/09/2024] Open
Abstract
In eukaryotic cells, gene expression begins with transcription in the nucleus, followed by the maturation of messenger RNAs (mRNAs). These mRNA molecules are then exported to the cytoplasm through the nuclear pore complex (NPC), a process that serves as a critical regulatory phase of gene expression. The export of mRNA is intricately linked to precursor mRNA (pre-mRNA) processing, ensuring that only properly processed mRNA reaches the cytoplasm. This coordination is essential, as recent studies have revealed that mRNA export factors not only assist in transport but also influence upstream processing steps, adding a layer of complexity to gene regulation. Furthermore, the export process competes with RNA processing and degradation pathways, maintaining a delicate balance vital for accurate gene expression. While these mechanisms are generally conserved across eukaryotes, significant differences exist between yeast and higher eukaryotic cells, particularly due to the more genome complexity of the latter. This review delves into the current research on mRNA export in higher eukaryotic cells, focusing on its role in the broader context of gene expression regulation and highlighting how it interacts with other gene expression processes to ensure precise and efficient gene functionality in complex organisms.
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Affiliation(s)
- Suli Chen
- Key Laboratory of Systems Health Science of Zhejiang ProvinceSchool of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou310024China
| | - Qingyi Jiang
- Key Laboratory of RNA InnovationScience and EngineeringShanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai200031China
| | - Jing Fan
- Key Laboratory of RNA InnovationScience and EngineeringShanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai200031China
- The Key Laboratory of Developmental Genes and Human DiseaseSchool of Life Science and TechnologySoutheast UniversityNanjing210096China
| | - Hong Cheng
- Key Laboratory of Systems Health Science of Zhejiang ProvinceSchool of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou310024China
- Key Laboratory of RNA InnovationScience and EngineeringShanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai200031China
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Khan I, Amin MA, Eklund EA, Gartel AL. Regulation of HOX gene expression in AML. Blood Cancer J 2024; 14:42. [PMID: 38453907 PMCID: PMC10920644 DOI: 10.1038/s41408-024-01004-y] [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: 11/27/2023] [Revised: 02/12/2024] [Accepted: 02/14/2024] [Indexed: 03/09/2024] Open
Abstract
As key developmental regulators, HOX cluster genes have varied and context-specific roles in normal and malignant hematopoiesis. A complex interaction of transcription factors, epigenetic regulators, long non-coding RNAs and chromatin structural changes orchestrate HOX expression in leukemia cells. In this review we summarize molecular mechanisms underlying HOX regulation in clinical subsets of AML, with a focus on NPM1 mutated (NPM1mut) AML comprising a third of all AML patients. While the leukemia initiating function of the NPM1 mutation is clearly dependent on HOX activity, the favorable treatment responses in these patients with upregulation of HOX cluster genes is a poorly understood paradoxical observation. Recent data confirm FOXM1 as a suppressor of HOX activity and a well-known binding partner of NPM suggesting that FOXM1 inactivation may mediate the effect of cytoplasmic NPM on HOX upregulation. Conversely the residual nuclear fraction of mutant NPM has also been recently shown to have chromatin modifying effects permissive to HOX expression. Recent identification of the menin-MLL interaction as a critical vulnerability of HOX-dependent AML has fueled the development of menin inhibitors that are clinically active in NPM1 and MLL rearranged AML despite inconsistent suppression of the HOX locus. Insights into context-specific regulation of HOX in AML may provide a solid foundation for targeting this common vulnerability across several major AML subtypes.
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Affiliation(s)
- Irum Khan
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
- Department of Medicine at the Feinberg School of Medicine, Northwestern University, Chicago, USA
| | - Mohammed A Amin
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Elizabeth A Eklund
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
- Department of Medicine at the Feinberg School of Medicine, Northwestern University, Chicago, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Andrei L Gartel
- Department of Medicine, University of Illinois, Chicago, IL, USA.
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Keuenhof KS, Kohler V, Broeskamp F, Panagaki D, Speese SD, Büttner S, Höög JL. Nuclear envelope budding and its cellular functions. Nucleus 2023; 14:2178184. [PMID: 36814098 PMCID: PMC9980700 DOI: 10.1080/19491034.2023.2178184] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 02/03/2023] [Indexed: 02/24/2023] Open
Abstract
The nuclear pore complex (NPC) has long been assumed to be the sole route across the nuclear envelope, and under normal homeostatic conditions it is indeed the main mechanism of nucleo-cytoplasmic transport. However, it has also been known that e.g. herpesviruses cross the nuclear envelope utilizing a pathway entitled nuclear egress or envelopment/de-envelopment. Despite this, a thread of observations suggests that mechanisms similar to viral egress may be transiently used also in healthy cells. It has since been proposed that mechanisms like nuclear envelope budding (NEB) can facilitate the transport of RNA granules, aggregated proteins, inner nuclear membrane proteins, and mis-assembled NPCs. Herein, we will summarize the known roles of NEB as a physiological and intrinsic cellular feature and highlight the many unanswered questions surrounding these intriguing nuclear events.
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Affiliation(s)
| | - Verena Kohler
- Institute of Molecular Biosciences, University of Graz, Austria
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Sweden
| | - Filomena Broeskamp
- Department for Chemistry and Molecular biology, University of Gothenburg, Sweden
| | - Dimitra Panagaki
- Department for Chemistry and Molecular biology, University of Gothenburg, Sweden
| | - Sean D. Speese
- Knight Cancer Early Detection Advanced Research Center, Oregon Health and Science University, 2720 S Moody Ave, Portland, OR, 97201, USA
| | - Sabrina Büttner
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Sweden
| | - Johanna L. Höög
- Department for Chemistry and Molecular biology, University of Gothenburg, Sweden
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Yang Y, Guo L, Chen L, Gong B, Jia D, Sun Q. Nuclear transport proteins: structure, function, and disease relevance. Signal Transduct Target Ther 2023; 8:425. [PMID: 37945593 PMCID: PMC10636164 DOI: 10.1038/s41392-023-01649-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 09/13/2023] [Accepted: 09/14/2023] [Indexed: 11/12/2023] Open
Abstract
Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport is a fundamental cellular process that regulates the localization of many macromolecules within the nuclear or cytoplasmic compartments. In humans, approximately 60 proteins are involved in nuclear transport, including nucleoporins that form membrane-embedded nuclear pore complexes, karyopherins that transport cargoes through these complexes, and Ran system proteins that ensure directed and rapid transport. Many of these nuclear transport proteins play additional and essential roles in mitosis, biomolecular condensation, and gene transcription. Dysregulation of nuclear transport is linked to major human diseases such as cancer, neurodegenerative diseases, and viral infections. Selinexor (KPT-330), an inhibitor targeting the nuclear export factor XPO1 (also known as CRM1), was approved in 2019 to treat two types of blood cancers, and dozens of clinical trials of are ongoing. This review summarizes approximately three decades of research data in this field but focuses on the structure and function of individual nuclear transport proteins from recent studies, providing a cutting-edge and holistic view on the role of nuclear transport proteins in health and disease. In-depth knowledge of this rapidly evolving field has the potential to bring new insights into fundamental biology, pathogenic mechanisms, and therapeutic approaches.
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Affiliation(s)
- Yang Yang
- Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lu Guo
- Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lin Chen
- Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Bo Gong
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Da Jia
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
| | - Qingxiang Sun
- Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
- Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre of Biotherapy, Chengdu, China.
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9
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Shen Y, Yang D, Zhang R, Chen X, Ma Q, Wei J, Zhai W, Pang A, He Y, Jiang E, Feng S. The outcome of acute leukemia patients with SET-NUP214 fusion after allogeneic stem cell transplantation. Front Oncol 2023; 13:1256043. [PMID: 37901324 PMCID: PMC10611484 DOI: 10.3389/fonc.2023.1256043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 09/25/2023] [Indexed: 10/31/2023] Open
Abstract
SET-NUP214 fusion gene, also known as TAF-1-CAN and SET-CAN, is observed in acute myeloid leukemia (AML) and T-cell lymphoblastic leukemia (T-ALL). SET-NUP214 fusion in T-cell lymphoblastic leukemia is associated with chemotherapy resistance, but the prognosis of patients with AML with SET-NUP214 has rarely been reported. In the present study, we retrospectively analyzed all patients with acute leukemia including AML and T-ALL patients with SET-NUP214 fusion who underwent allogeneic stem cell transplantation (alloHSCT) in our center from July 2017 to November 2022. Of the total 11 patients, 5 patients were diagnosed with AML and 6 patients were diagnosed with T-ALL de novo. All patients received myeloablative regimens in CR1, and there were three (60%) AML patients who relapsed post-alloHSCT and three T-ALL (50%) patients who relapsed post-alloHSCT. Only one patient with AML who relapsed post-alloHSCT responded to subsequent chemotherapy plus donor lymphocyte infusion and survived the last follow-up. The estimated 1-year overall survival and 3-year overall survival for all these 11 patients were 69.3% and 38.5%, respectively. The estimated 1-year leukemia-free survival and 3-year leukemia-free survival for all patients were 69.3% and 38.5%, respectively. The research shows a high incidence of relapse for patients with acute leukemia with the SET-NUP214 fusion gene, even after alloHSCT. More clinical trials or research with larger samples are urgently needed for this group of patients.
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Affiliation(s)
- Yuyan Shen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Donglin Yang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Rongli Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Xin Chen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Qiaoling Ma
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Jialin Wei
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Weihua Zhai
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Aiming Pang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Yi He
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Erlie Jiang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Sizhou Feng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
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10
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Dave A, Park EJ, Pezzuto JM. Multi-Organ Nutrigenomic Effects of Dietary Grapes in a Mouse Model. Antioxidants (Basel) 2023; 12:1821. [PMID: 37891900 PMCID: PMC10604885 DOI: 10.3390/antiox12101821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
As a whole food, the potential health benefits of table grapes have been widely studied. Some individual constituents have garnered great attention, particularly resveratrol, but normal quantities in the diet are meniscal. On the other hand, the grape contains hundreds of compounds, many of which have antioxidant potential. Nonetheless, the achievement of serum or tissue concentrations of grape antioxidants sufficient to mediate a direct quenching effect is not likely, which supports the idea of biological responses being mediated by an indirect catalytic-type response. We demonstrate herein with Hsd:ICR (CD-1® Outbred, 18-24 g, 3-4 weeks old, female) mice that supplementation of a semi-synthetic diet with a grape surrogate, equivalent to the human consumption of 2.5 servings per day for 12 months, modulates gene expression in the liver, kidney, colon, and ovary. As might be expected when sampling changes in a pool of over 35,000 genes, there are numerous functional implications. Analysis of some specific differentially expressed genes suggests the potential of grape consumption to bolster metabolic detoxification and regulation of reactive oxygen species in the liver, cellular metabolism, and anti-inflammatory activity in the ovary and kidney. In the colon, the data suggest anti-inflammatory activity, suppression of mitochondrial dysfunction, and maintaining homeostasis. Pathway analysis reveals a combination of up- and down-regulation in the target tissues, primarily up-regulated in the kidney and down-regulated in the ovary. More broadly, based on these data, it seems logical to conclude that grape consumption leads to modulation of gene expression throughout the body, the consequence of which may help to explain the broad array of activities demonstrated in diverse tissues such as the brain, heart, eye, bladder, and colon. In addition, this work further supports the profound impact of nutrigenomics on mammalian phenotypic expression.
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Affiliation(s)
- Asim Dave
- Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USA; (A.D.); (E.-J.P.)
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Eun-Jung Park
- Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USA; (A.D.); (E.-J.P.)
- Department of Pharmaceutical and Administrative Science, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA
| | - John M. Pezzuto
- College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA
- Department of Medicine, UMass Chan Medical School—Baystate, Springfield, MA 01199, USA
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11
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Cui H, Sun X, Schilling M, Herold‐Mende C, Reischl M, Levkin PA, Popova AA, Turcan Ş. Repurposing FDA-Approved Drugs for Temozolomide-Resistant IDH1 Mutant Glioma Using High-Throughput Miniaturized Screening on Droplet Microarray Chip. Adv Healthc Mater 2023; 12:e2300591. [PMID: 37162029 PMCID: PMC11469062 DOI: 10.1002/adhm.202300591] [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: 02/23/2023] [Revised: 04/25/2023] [Indexed: 05/11/2023]
Abstract
To address the challenge of drug resistance and limited treatment options for recurrent gliomas with IDH1 mutations, a highly miniaturized screening of 2208 FDA-approved drugs is conducted using a high-throughput droplet microarray (DMA) platform. Two patient-derived temozolomide-resistant tumorspheres harboring endogenous IDH1 mutations (IDH1mut ) are utilized. Screening identifies over 20 drugs, including verteporfin (VP), that significantly affected tumorsphere formation and viability. Proteomics analysis reveals that nuclear pore complex may be a potential VP target, suggesting a new mechanism of action independent of its known effects on YAP1. Knockdown experiments exclude YAP1 as a drug target in tumorspheres. Pathway analysis shows that NUP107 is a potential upstream regulator associated with VP response. Analysis of publicly available genomic datasets shows a significant correlation between high NUP107 expression and decreased survival in IDH1mut astrocytoma, suggesting NUP107 may be a potential biomarker for VP response. This study demonstrates a miniaturized approach for cost-effective drug repurposing using 3D glioma models and identifies nuclear pore complex as a potential target for drug development. The findings provide preclinical evidence to support in vivo and clinical studies of VP and other identified compounds to treat IDH1mut gliomas, which may ultimately improve clinical outcomes for patients with this challenging disease.
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Affiliation(s)
- Haijun Cui
- Institute of Biological and Chemical Systems – Functional Molecular Systems (IBCS‐FMS)Karlsruhe Institute of Technology (KIT)Hermann‐von‐Helmholtz‐Platz 176344Eggenstein‐LeopoldshafenGermany
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044China
| | - Xueyuan Sun
- Neurology Clinic and National Center for Tumor DiseasesUniversity Hospital HeidelbergIm Neuenheimer Feld 40069120HeidelbergGermany
| | - Marcel Schilling
- Institute for Automation and Applied Informatics (IAI)Karlsruhe Institute of Technology (KIT)Hermann‐von‐Helmholtz‐Platz 176344Eggenstein‐LeopoldshafenGermany
| | - Christel Herold‐Mende
- Neurology Clinic and National Center for Tumor DiseasesUniversity Hospital HeidelbergIm Neuenheimer Feld 40069120HeidelbergGermany
| | - Markus Reischl
- Institute for Automation and Applied Informatics (IAI)Karlsruhe Institute of Technology (KIT)Hermann‐von‐Helmholtz‐Platz 176344Eggenstein‐LeopoldshafenGermany
| | - Pavel A. Levkin
- Institute of Biological and Chemical Systems – Functional Molecular Systems (IBCS‐FMS)Karlsruhe Institute of Technology (KIT)Hermann‐von‐Helmholtz‐Platz 176344Eggenstein‐LeopoldshafenGermany
- Institute of Organic Chemistry (IOC)Karlsruhe Institute of Technology (KIT)Fritz‐Haber Weg 676131KarlsruheGermany
| | - Anna A. Popova
- Institute of Biological and Chemical Systems – Functional Molecular Systems (IBCS‐FMS)Karlsruhe Institute of Technology (KIT)Hermann‐von‐Helmholtz‐Platz 176344Eggenstein‐LeopoldshafenGermany
| | - Şevin Turcan
- Neurology Clinic and National Center for Tumor DiseasesUniversity Hospital HeidelbergIm Neuenheimer Feld 40069120HeidelbergGermany
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12
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Oka M, Otani M, Miyamoto Y, Oshima R, Adachi J, Tomonaga T, Asally M, Nagaoka Y, Tanaka K, Toyoda A, Ichikawa K, Morishita S, Isono K, Koseki H, Nakato R, Ohkawa Y, Yoneda Y. Phase-separated nuclear bodies of nucleoporin fusions promote condensation of MLL1/CRM1 and rearrangement of 3D genome structure. Cell Rep 2023; 42:112884. [PMID: 37516964 DOI: 10.1016/j.celrep.2023.112884] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 05/29/2023] [Accepted: 07/13/2023] [Indexed: 08/01/2023] Open
Abstract
NUP98 and NUP214 form chimeric fusion proteins that assemble into phase-separated nuclear bodies containing CRM1, a nuclear export receptor. However, these nuclear bodies' function in controlling gene expression remains elusive. Here, we demonstrate that the nuclear bodies of NUP98::HOXA9 and SET::NUP214 promote the condensation of mixed lineage leukemia 1 (MLL1), a histone methyltransferase essential for the maintenance of HOX gene expression. These nuclear bodies are robustly associated with MLL1/CRM1 and co-localized on chromatin. Furthermore, whole-genome chromatin-conformation capture analysis reveals that NUP98::HOXA9 induces a drastic alteration in high-order genome structure at target regions concomitant with the generation of chromatin loops and/or rearrangement of topologically associating domains in a phase-separation-dependent manner. Collectively, these results show that the phase-separated nuclear bodies of nucleoporin fusion proteins can enhance the activation of target genes by promoting the condensation of MLL1/CRM1 and rearrangement of the 3D genome structure.
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Affiliation(s)
- Masahiro Oka
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan.
| | - Mayumi Otani
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
| | - Yoichi Miyamoto
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
| | - Rieko Oshima
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
| | - Jun Adachi
- Laboratory of Proteomics for Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
| | - Takeshi Tomonaga
- Laboratory of Proteomics for Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
| | - Munehiro Asally
- School of Life Sciences, The University of Warwick, Coventry CV4 7AL, UK
| | - Yuya Nagaoka
- Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Kaori Tanaka
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan
| | - Atsushi Toyoda
- Advanced Genomics Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan
| | - Kazuki Ichikawa
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8568, Japan
| | - Shinichi Morishita
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8568, Japan
| | - Kyoichi Isono
- Laboratory Animal Center, Wakayama Medical University, 811-1 Kimi-idera, Wakayama 641-8509, Japan
| | - Haruhiko Koseki
- Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
| | - Ryuichiro Nakato
- Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
| | - Yasuyuki Ohkawa
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
| | - Yoshihiro Yoneda
- National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
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13
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Singh U, Bindra D, Samaiya A, Mishra RK. Overexpressed Nup88 stabilized through interaction with Nup62 promotes NF-κB dependent pathways in cancer. Front Oncol 2023; 13:1095046. [PMID: 36845732 PMCID: PMC9947638 DOI: 10.3389/fonc.2023.1095046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/16/2023] [Indexed: 02/11/2023] Open
Abstract
Bidirectional nucleo-cytoplasmic transport, regulating several vital cellular processes, is mediated by the Nuclear Pore Complex (NPC) comprising the nucleoporin (Nup) proteins. Nup88, a constituent nucleoporin, is overexpressed in many cancers, and a positive correlation exists between progressive stages of cancer and Nup88 levels. While a significant link of Nup88 overexpression in head and neck cancer exists but mechanistic details of Nup88 roles in tumorigenesis are sparse. Here, we report that Nup88 and Nup62 levels are significantly elevated in head and neck cancer patient samples and cell lines. We demonstrate that the elevated levels of Nup88 or Nup62 impart proliferation and migration advantages to cells. Interestingly, Nup88-Nup62 engage in a strong interaction independent of Nup-glycosylation status and cell-cycle stages. We report that the interaction with Nup62 stabilizes Nup88 by inhibiting the proteasome-mediated degradation of overexpressed Nup88. Overexpressed Nup88 stabilized by interaction with Nup62 can interact with NF-κB (p65) and sequesters p65 partly into nucleus of unstimulated cells. NF-κB targets like Akt, c-myc, IL-6 and BIRC3 promoting proliferation and growth are induced under Nup88 overexpression conditions. In conclusion, our data indicates that simultaneous overexpression of Nup62 and Nup88 in head and neck cancer stabilizes Nup88. Stabilized Nup88 interacts and activates p65 pathway, which perhaps is the underlying mechanism in Nup88 overexpressing tumors.
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Affiliation(s)
- Usha Singh
- Nups and Sumo Biology Group, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh, India
| | - Divya Bindra
- Nups and Sumo Biology Group, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh, India
| | - Atul Samaiya
- Department of Surgical Oncology, Bansal Hospital, Bhopal, Madhya Pradesh, India
| | - Ram Kumar Mishra
- Nups and Sumo Biology Group, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh, India,*Correspondence: Ram Kumar Mishra,
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14
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Scott NR, Parekh SH. A-type lamins involvement in transport and implications in cancer? Nucleus 2022; 13:221-235. [PMID: 36109835 PMCID: PMC9481127 DOI: 10.1080/19491034.2022.2118418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Nuclear lamins and transport are intrinsically linked, but their relationship is yet to be fully unraveled. A multitude of complex, coupled interactions between lamins and nucleoporins (Nups), which mediate active transport into and out of the nucleus, combined with well documented dysregulation of lamins in many cancers, suggests that lamins and nuclear transport may play a pivotal role in carcinogenesis and the preservation of cancer. Changes of function related to lamin/Nup activity can principally lead to DNA damage, further increasing the genetic diversity within a tumor, which could lead to the reduction the effectiveness of antineoplastic treatments. This review discusses and synthesizes different connections of lamins to nuclear transport and offers a number of outlook questions, the answers to which could reveal a new perspective on the connection of lamins to molecular transport of cancer therapeutics, in addition to their established role in nuclear mechanics.
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Affiliation(s)
- Nicholas R. Scott
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA
| | - Sapun H. Parekh
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA
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15
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Petrovic S, Mobbs GW, Bley CJ, Nie S, Patke A, Hoelz A. Structure and Function of the Nuclear Pore Complex. Cold Spring Harb Perspect Biol 2022; 14:a041264. [PMID: 36096637 PMCID: PMC9732903 DOI: 10.1101/cshperspect.a041264] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The nucleus, a genome-containing organelle eponymous of eukaryotes, is enclosed by a double membrane continuous with the endoplasmic reticulum. The nuclear pore complex (NPC) is an ∼110-MDa, ∼1000-protein channel that selectively transports macromolecules across the nuclear envelope and thus plays a central role in the regulated flow of genetic information from transcription to translation. Its size, complexity, and flexibility have hindered determination of atomistic structures of intact NPCs. Recent studies have overcome these hurdles by combining biochemical reconstitution and docking of high-resolution structures of NPC subcomplexes into cryo-electron tomographic reconstructions with biochemical and physiological validation. Here, we provide an overview of the near-atomic composite structure of the human NPC, a milestone toward unlocking a molecular understanding of mRNA export, NPC-associated diseases, and viral host-pathogen interactions, serving as a paradigm for studying similarly large complexes.
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Affiliation(s)
- Stefan Petrovic
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - George W Mobbs
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - Christopher J Bley
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - Si Nie
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - Alina Patke
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - André Hoelz
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
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16
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Bierzynska A, Bull K, Miellet S, Dean P, Neal C, Colby E, McCarthy HJ, Hegde S, Sinha MD, Bugarin Diz C, Stirrups K, Megy K, Mapeta R, Penkett C, Marsh S, Forrester N, Afzal M, Stark H, BioResource NIHR, Williams M, Welsh GI, Koziell AB, Hartley PS, Saleem MA. Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model. Pediatr Nephrol 2022; 37:2643-2656. [PMID: 35211795 PMCID: PMC9489583 DOI: 10.1007/s00467-022-05440-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 12/10/2021] [Accepted: 12/21/2021] [Indexed: 10/24/2022]
Abstract
BACKGROUND Variants in genes encoding nuclear pore complex (NPC) proteins are a newly identified cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent reports describing NUP93 variants suggest these could be a significant cause of paediatric onset SRNS. We report NUP93 cases in the UK and demonstrate in vivo functional effects of Nup93 depletion in a fly (Drosophila melanogaster) nephrocyte model. METHODS Three hundred thirty-seven paediatric SRNS patients from the National cohort of patients with Nephrotic Syndrome (NephroS) were whole exome and/or whole genome sequenced. Patients were screened for over 70 genes known to be associated with Nephrotic Syndrome (NS). D. melanogaster Nup93 knockdown was achieved by RNA interference using nephrocyte-restricted drivers. RESULTS Six novel homozygous and compound heterozygous NUP93 variants were detected in 3 sporadic and 2 familial paediatric onset SRNS characterised histologically by focal segmental glomerulosclerosis (FSGS) and progressing to kidney failure by 12 months from clinical diagnosis. Silencing of the two orthologs of human NUP93 expressed in D. melanogaster, Nup93-1, and Nup93-2 resulted in significant signal reduction of up to 82% in adult pericardial nephrocytes with concomitant disruption of NPC protein expression. Additionally, nephrocyte morphology was highly abnormal in Nup93-1 and Nup93-2 silenced flies surviving to adulthood. CONCLUSION We expand the spectrum of NUP93 variants detected in paediatric onset SRNS and demonstrate its incidence within a national cohort. Silencing of either D. melanogaster Nup93 ortholog caused a severe nephrocyte phenotype, signaling an important role for the nucleoporin complex in podocyte biology. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Agnieszka Bierzynska
- Bristol Renal and Children’s Renal Unit, Bristol Medical School, University of Bristol, Whitson Street, Bristol, BS1 3NY UK
| | - Katherine Bull
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Sara Miellet
- Department of Life and Environmental Science, Bournemouth University, Talbot Campus, Fern Barrow, Poole, Dorset BH12 5BB England, UK
- Illawarra Health and Medical Research Institute, Molecular Horizons and School of Medicine, University of Wollongong, Wollongong, Australia
| | - Philip Dean
- Bristol Genetics Laboratory, North Bristol National Health Service Trust, Bristol, UK
| | - Chris Neal
- Bristol Renal and Children’s Renal Unit, Bristol Medical School, University of Bristol, Whitson Street, Bristol, BS1 3NY UK
| | - Elizabeth Colby
- Bristol Renal and Children’s Renal Unit, Bristol Medical School, University of Bristol, Whitson Street, Bristol, BS1 3NY UK
| | - Hugh J. McCarthy
- Bristol Renal and Children’s Renal Unit, Bristol Medical School, University of Bristol, Whitson Street, Bristol, BS1 3NY UK
- School of Medicine, University of Sydney and Children’s Hospital at Westmead, Westmead, Australia
| | - Shivaram Hegde
- Children’s Kidney Centre, University Hospital of Wales, Cardiff, UK
| | - Manish D. Sinha
- Department of Paediatric Nephrology, Evelina London Children’s Hospital, Guy’s and St, Thomas’ Hospital, London, UK
| | - Carmen Bugarin Diz
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, SE1 7EH UK
| | - Kathleen Stirrups
- NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, CB2 0QQ UK
| | - Karyn Megy
- NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, CB2 0QQ UK
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Rutendo Mapeta
- NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, CB2 0QQ UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK
| | - Chris Penkett
- NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, CB2 0QQ UK
| | - Sarah Marsh
- Bristol Genetics Laboratory, North Bristol National Health Service Trust, Bristol, UK
| | - Natalie Forrester
- Illawarra Health and Medical Research Institute, Molecular Horizons and School of Medicine, University of Wollongong, Wollongong, Australia
| | - Maryam Afzal
- Bristol Renal and Children’s Renal Unit, Bristol Medical School, University of Bristol, Whitson Street, Bristol, BS1 3NY UK
| | - Hannah Stark
- NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, CB2 0QQ UK
| | - NIHR BioResource
- NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, CB2 0QQ UK
| | - Maggie Williams
- Bristol Genetics Laboratory, North Bristol National Health Service Trust, Bristol, UK
| | - Gavin I. Welsh
- Bristol Renal and Children’s Renal Unit, Bristol Medical School, University of Bristol, Whitson Street, Bristol, BS1 3NY UK
| | - Ania B. Koziell
- Department of Paediatric Nephrology, Evelina London Children’s Hospital, Guy’s and St, Thomas’ Hospital, London, UK
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, SE1 7EH UK
| | - Paul S. Hartley
- Department of Life and Environmental Science, Bournemouth University, Talbot Campus, Fern Barrow, Poole, Dorset BH12 5BB England, UK
| | - Moin A. Saleem
- Bristol Renal and Children’s Renal Unit, Bristol Medical School, University of Bristol, Whitson Street, Bristol, BS1 3NY UK
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17
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Xie W, Raess PW, Dunlap J, Hoyos CM, Li H, Li P, Swords R, Olson SB, Yang F, Anekpuritanang T, Hu S, Wiszniewska J, Fan G, Press RD, Moore SR. Adult acute myeloid leukemia patients with NUP98 rearrangement have frequent cryptic translocations and unfavorable outcome. Leuk Lymphoma 2022; 63:1907-1916. [DOI: 10.1080/10428194.2022.2047672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Wei Xie
- Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Philipp W. Raess
- Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Jennifer Dunlap
- Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Cristina Magallanes Hoyos
- Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Hongmei Li
- Pathology and Laboratory, and North Shore Pathologists, Ascension Wisconsin Health Care, Milwaukee, WI, USA
| | - Peng Li
- University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Ronan Swords
- Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, OR, USA
| | - Susan B. Olson
- Knight Diagnostic Laboratories, Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
| | - Fei Yang
- Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Tauangtham Anekpuritanang
- Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR, USA
- Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Shimin Hu
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joanna Wiszniewska
- Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Guang Fan
- Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Richard D. Press
- Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Stephen R. Moore
- Knight Diagnostic Laboratories, Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
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18
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Pulianmackal AJ, Kanakousaki K, Flegel K, Grushko OG, Gourley E, Rozich E, Buttitta LA. Misregulation of Nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesis. Dis Model Mech 2022; 15:dmm049234. [PMID: 35107131 PMCID: PMC8938402 DOI: 10.1242/dmm.049234] [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: 08/03/2021] [Accepted: 01/15/2022] [Indexed: 11/20/2022] Open
Abstract
Nucleoporin 98KD (Nup98) is a promiscuous translocation partner in hematological malignancies. Most disease models of Nup98 translocations involve ectopic expression of the fusion protein under study, leaving the endogenous Nup98 loci unperturbed. Overlooked in these approaches is the loss of one copy of normal Nup98 in addition to the loss of Nup96 - a second Nucleoporin encoded within the same mRNA and reading frame as Nup98 - in translocations. Nup98 and Nup96 are also mutated in a number of other cancers, suggesting that their disruption is not limited to blood cancers. We found that reducing Nup98-96 function in Drosophila melanogaster (in which the Nup98-96 shared mRNA and reading frame is conserved) de-regulates the cell cycle. We found evidence of overproliferation in tissues with reduced Nup98-96, counteracted by elevated apoptosis and aberrant signaling associated with chronic wounding. Reducing Nup98-96 function led to defects in protein synthesis that triggered JNK signaling and contributed to hallmarks of tumorigenesis when apoptosis was inhibited. We suggest that partial loss of Nup98-96 function in translocations could de-regulate protein synthesis, leading to signaling that cooperates with other mutations to promote tumorigenesis.
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Affiliation(s)
| | | | | | | | | | | | - Laura A. Buttitta
- Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
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19
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In focus in HCB. Histochem Cell Biol 2021; 156:405-408. [PMID: 34729665 DOI: 10.1007/s00418-021-02044-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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20
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Chen M, Long Q, Borrie MS, Sun H, Zhang C, Yang H, Shi D, Gartenberg MR, Deng W. Nucleoporin TPR promotes tRNA nuclear export and protein synthesis in lung cancer cells. PLoS Genet 2021; 17:e1009899. [PMID: 34793452 PMCID: PMC8639082 DOI: 10.1371/journal.pgen.1009899] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 12/02/2021] [Accepted: 10/21/2021] [Indexed: 12/26/2022] Open
Abstract
The robust proliferation of cancer cells requires vastly elevated levels of protein synthesis, which relies on a steady supply of aminoacylated tRNAs. Delivery of tRNAs to the cytoplasm is a highly regulated process, but the machinery for tRNA nuclear export is not fully elucidated. In this study, using a live cell imaging strategy that visualizes nascent transcripts from a specific tRNA gene in yeast, we identified the nuclear basket proteins Mlp1 and Mlp2, two homologs of the human TPR protein, as regulators of tRNA export. TPR expression is significantly increased in lung cancer tissues and correlated with poor prognosis. Consistently, knockdown of TPR inhibits tRNA nuclear export, protein synthesis and cell growth in lung cancer cell lines. We further show that NXF1, a well-known mRNA nuclear export factor, associates with tRNAs and mediates their transport through nuclear pores. Collectively, our findings uncover a conserved mechanism that regulates nuclear export of tRNAs, which is a limiting step in protein synthesis in eukaryotes.
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Affiliation(s)
- Miao Chen
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America
| | - Qian Long
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Melinda S. Borrie
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America
| | - Haohui Sun
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Changlin Zhang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Obstetrics and Gynecology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Han Yang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Dingbo Shi
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Marc R. Gartenberg
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America
- The Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey, United States of America
| | - Wuguo Deng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
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21
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Overexpression of the nucleoporin Nup88 stimulates migration and invasion of HeLa cells. Histochem Cell Biol 2021; 156:409-421. [PMID: 34331103 PMCID: PMC8604841 DOI: 10.1007/s00418-021-02020-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2021] [Indexed: 12/11/2022]
Abstract
Elevated expression of the nucleoporin Nup88, a constituent of the nuclear pore complex, is seen in various types of malignant tumors, but whether this overexpression contributes to the malignant phenotype has yet to be determined. Here, we investigated the effect of the overexpression of Nup88 on the migration and invasion of cervical cancer HeLa cells. The overexpression of Nup88 promoted a slight but significant increase in both migration and invasion, whereas knockdown of Nup88 by RNA interference suppressed these phenotypes. The observed phenotypes in Nup88-overexpressing HeLa cells were not due to the progression of the epithelial-to-mesenchymal transition or activation of NF-κB, which are known to be important for cell migration and invasion. Instead, we identified an upregulation of matrix metalloproteinase-12 (MMP-12) at both the gene and protein levels in Nup88-overexpressing HeLa cells. Upregulation of MMP-12 protein by the overexpression of Nup88 was also observed in one other cervical cancer cell line and two prostate cancer cell lines but not 293 cells. Treatment with a selective inhibitor against MMP-12 enzymatic activity significantly suppressed the invasive ability of HeLa cells induced by Nup88 overexpression. Taken together, our results suggest that overexpression of Nup88 can stimulate malignant phenotypes including invasive ability, which is promoted by MMP-12 expression.
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22
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Explaining Ovarian Cancer Gene Expression Profiles with Fuzzy Rules and Genetic Algorithms. ELECTRONICS 2021. [DOI: 10.3390/electronics10040375] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The analysis of gene expression data is a complex task, and many tools and pipelines are available to handle big sequencing datasets for case-control (bivariate) studies. In some cases, such as pilot or exploratory studies, the researcher needs to compare more than two groups of samples consisting of a few replicates. Both standard statistical bioinformatic pipelines and innovative deep learning models are unsuitable for extracting interpretable patterns and information from such datasets. In this work, we apply a combination of fuzzy rule systems and genetic algorithms to analyze a dataset composed of 21 samples and 6 classes, useful for approaching the study of expression profiles in ovarian cancer, compared to other ovarian diseases. The proposed method is capable of performing a feature selection among genes that is guided by the genetic algorithm, and of building a set of if-then rules that explain how classes can be distinguished by observing changes in the expression of selected genes. After testing several parameters, the final model consists of 10 genes involved in the molecular pathways of cancer and 10 rules that correctly classify all samples.
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23
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The Nuclear Pore Complex and mRNA Export in Cancer. Cancers (Basel) 2020; 13:cancers13010042. [PMID: 33375634 PMCID: PMC7796397 DOI: 10.3390/cancers13010042] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/11/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023] Open
Abstract
Export of mRNAs from the nucleus to the cytoplasm is a key regulatory step in the expression of proteins. mRNAs are transported through the nuclear pore complex (NPC). Export of mRNAs responds to a variety of cellular stimuli and stresses. Revelations of the specific effects elicited by NPC components and associated co-factors provides a molecular basis for the export of selected RNAs, independent of bulk mRNA export. Aberrant RNA export has been observed in primary human cancer specimens. These cargo RNAs encode factors involved in nearly all facets of malignancy. Indeed, the NPC components involved in RNA export as well as the RNA export machinery can be found to be dysregulated, mutated, or impacted by chromosomal translocations in cancer. The basic mechanisms associated with RNA export with relation to export machinery and relevant NPC components are described. Therapeutic strategies targeting this machinery in clinical trials is also discussed. These findings firmly position RNA export as a targetable feature of cancer along with transcription and translation.
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24
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dBMHCC: A comprehensive hepatocellular carcinoma (HCC) biomarker database provides a reliable prediction system for novel HCC phosphorylated biomarkers. PLoS One 2020; 15:e0234084. [PMID: 32497121 PMCID: PMC7272086 DOI: 10.1371/journal.pone.0234084] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 05/18/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC), which is associated with an absence of obvious symptoms and poor prognosis, is the second leading cause of cancer death worldwide. Genome-wide molecular biology studies should provide biological insights into HCC development. Based on the importance of phosphorylation for signal transduction, several protein kinase inhibitors have been developed that improve the survival of cancer patients. However, a comprehensive database of HCC-related phosphorylated biomarkers (HCCPMs) and novel HCCPMs prediction platform has been lacking. We have thus constructed the dBMHCC databases to provide expression profiles, phosphorylation and drug information, and evidence type; gathered information on HCC-related pathways and their involved genes as candidate HCC biomarkers; and established a system for evaluating protein phosphorylation and HCC-related biomarkers to improve the reliability of biomarker prediction. The resulting dBMHCC contains 611 notable HCC-related genes, 234 HCC-related pathways, 17 phosphorylation-related motifs and their 255 corresponding protein kinases, 5955 HCC biomarkers, and 1077 predicted HCCPMs. Methionine adenosyltransferase 2B (MAT2B) and acireductone dioxygenase 1 (ADI1), which regulate HCC development and hepatitis C virus infection, respectively, were among the top 10 HCCPMs predicted by dBMHCC. Platelet-derived growth factor receptor alpha (PDGFRA), which had the highest evaluation score, was identified as the target of one HCC drug (Regorafenib), five cancer drugs, and four non-cancer drugs. dBMHCC is an open resource for HCC phosphorylated biomarkers, which supports researchers investigating the development of HCC and designing novel diagnosis methods and drug treatments. Database URL:http://predictor.nchu.edu.tw/dBMHCC.
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25
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Ouyang X, Hao X, Liu S, Hu J, Hu L. Expression of Nup93 is associated with the proliferation, migration and invasion capacity of cervical cancer cells. Acta Biochim Biophys Sin (Shanghai) 2019; 51:1276-1285. [PMID: 31774908 DOI: 10.1093/abbs/gmz131] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/30/2019] [Accepted: 10/07/2019] [Indexed: 01/15/2023] Open
Abstract
Cervical cancer is a prevalent and devastating malignancy in females worldwide. Nucleoporin 93 (Nup93), a member of the nuclear pore complex, plays an important role in transport across the nuclear pore. Several nucleoporins have been linked to cancer. However, the oncogenic role and underlying mechanism of Nup93 in cervical cancer development have not been reported. In this study, the expression of Nup93 was analyzed by quantitative real-time polymerase chain reaction (qPCR), western blot analysis, and immunohistochemical staining in cervical cancer tissues and cell lines. We found that the expression of Nup93 was higher in cervical cancer samples, compared to normal cervical samples. The knockdown of Nup93 inhibited cell proliferation, migration, and invasion capacity of cervical cancer cells. At the same time, we also found that silencing of Nup93 could inhibit cellular migration and invasion by regulating cytoskeleton actin and Rho family proteins. Nup93 also participated in the IL-6/STAT3 signaling pathway. In addition, down-regulation of Nup93 prevented tumor formation in mice in vivo. Thus, Nup93 may be a carcinogenic gene and serve as a potential therapeutic target for cervical cancer.
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Affiliation(s)
- Xiaolan Ouyang
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xiaoming Hao
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Shuaibin Liu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Jianguo Hu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Lina Hu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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26
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Oka M, Mura S, Otani M, Miyamoto Y, Nogami J, Maehara K, Harada A, Tachibana T, Yoneda Y, Ohkawa Y. Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells. eLife 2019; 8:e46667. [PMID: 31755865 PMCID: PMC6874418 DOI: 10.7554/elife.46667] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 10/30/2019] [Indexed: 12/14/2022] Open
Abstract
We previously demonstrated that CRM1, a major nuclear export factor, accumulates at Hox cluster regions to recruit nucleoporin-fusion protein Nup98HoxA9, resulting in robust activation of Hox genes (Oka et al., 2016). However, whether this phenomenon is general to other leukemogenic proteins remains unknown. Here, we show that two other leukemogenic proteins, nucleoporin-fusion SET-Nup214 and the NPM1 mutant, NPM1c, which contains a nuclear export signal (NES) at its C-terminus and is one of the most frequent mutations in acute myeloid leukemia, are recruited to the HOX cluster region via chromatin-bound CRM1, leading to HOX gene activation in human leukemia cells. Furthermore, we demonstrate that this mechanism is highly sensitive to a CRM1 inhibitor in leukemia cell line. Together, these findings indicate that CRM1 acts as a key molecule that connects leukemogenic proteins to aberrant HOX gene regulation either via nucleoporin-CRM1 interaction (for SET-Nup214) or NES-CRM1 interaction (for NPM1c).
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Affiliation(s)
- Masahiro Oka
- Laboratory of Nuclear Transport DynamicsNational Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)OsakaJapan
- Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical SciencesOsaka UniversityOsakaJapan
| | - Sonoko Mura
- Biomolecular Dynamics Group, Graduate School of Frontier BiosciencesOsaka UniversityOsakaJapan
| | - Mayumi Otani
- Laboratory of Nuclear Transport DynamicsNational Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)OsakaJapan
| | - Yoichi Miyamoto
- Laboratory of Nuclear Transport DynamicsNational Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)OsakaJapan
| | - Jumpei Nogami
- Department of Advanced Medical Initiatives, Faculty of MedicineKyushu UniversityFukuokaJapan
| | - Kazumitsu Maehara
- Department of Advanced Medical Initiatives, Faculty of MedicineKyushu UniversityFukuokaJapan
| | - Akihito Harada
- Department of Advanced Medical Initiatives, Faculty of MedicineKyushu UniversityFukuokaJapan
| | - Taro Tachibana
- Department of Bioengineering, Graduate School of EngineeringOsaka City UniversityOsakaJapan
| | - Yoshihiro Yoneda
- Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical SciencesOsaka UniversityOsakaJapan
- National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)OsakaJapan
| | - Yasuyuki Ohkawa
- Department of Advanced Medical Initiatives, Faculty of MedicineKyushu UniversityFukuokaJapan
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27
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Hanson PJ, Hossain AR, Qiu Y, Zhang HM, Zhao G, Li C, Lin V, Sulaimon S, Vlok M, Fung G, Chen VH, Jan E, McManus BM, Granville DJ, Yang D. Cleavage and Sub-Cellular Redistribution of Nuclear Pore Protein 98 by Coxsackievirus B3 Protease 2A Impairs Cardioprotection. Front Cell Infect Microbiol 2019; 9:265. [PMID: 31396490 PMCID: PMC6667557 DOI: 10.3389/fcimb.2019.00265] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 07/08/2019] [Indexed: 01/15/2023] Open
Abstract
Myocarditis, inflammation of the heart muscle, affects all demographics and is a major cause of sudden and unexpected death in young people. It is most commonly caused by viral infections of the heart, with coxsackievirus B3 (CVB3) being among the most prevalent pathogens. To understand the molecular pathogenesis of CVB3 infection and provide strategies for developing treatments, we examined the role of a key nuclear pore protein 98 (NUP98) in the setting of viral myocarditis. NUP98 was cleaved as early as 2 h post-CVB3 infection. This cleavage was further verified through both the ectopic expression of viral proteases and in vitro using purified recombinant CVB3 proteases (2A and 3C), which demonstrated that CVB3 2A but not 3C is responsible for this cleavage. By immunostaining and confocal imaging, we observed that cleavage resulted in the redistribution of NUP98 to punctate structures in the cytoplasm. Targeted siRNA knockdown of NUP98 during infection further increased viral protein expression and viral titer, and reduced cell viability, suggesting a potential antiviral role of NUP98. Moreover, we discovered that expression levels of neuregulin-1 (NRG1), a cardioprotective gene, and presenilin-1 (PSEN1), a cellular protease processing the tyrosine kinase receptor ERBB4 of NRG1, were reliant upon NUP98 and were downregulated during CVB3 infection. In addition, expression of these NUP98 target genes in myocardium tissue not only occurred at an earlier phase of infection, but also appeared in areas away from the initial inflammatory regions. Collectively, CVB3-induced cleavage of NUP98 and subsequent impairment of the cardioprotective NRG1-ERBB4/PSEN1 signaling cascade may contribute to increased myocardial damage in the context of CVB3-induced myocarditis. To our knowledge, this is the first study to demonstrate the link between NUP98 and the NRG1 signaling pathway in viral myocarditis.
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Affiliation(s)
- Paul J Hanson
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Al Rohet Hossain
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Ye Qiu
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Huifang M Zhang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Guangze Zhao
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Cheng Li
- UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Veena Lin
- UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Saheedat Sulaimon
- UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.,Jefferson College of Population Health, Thomas Jefferson University, Philadelphia, PA, United States
| | - Marli Vlok
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
| | - Gabriel Fung
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Victoria H Chen
- UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.,Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Eric Jan
- Jefferson College of Population Health, Thomas Jefferson University, Philadelphia, PA, United States
| | - Bruce M McManus
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.,Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - David J Granville
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Decheng Yang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
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28
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Alvarado-Kristensson M, Rosselló CA. The Biology of the Nuclear Envelope and Its Implications in Cancer Biology. Int J Mol Sci 2019; 20:E2586. [PMID: 31137762 PMCID: PMC6566445 DOI: 10.3390/ijms20102586] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 05/07/2019] [Accepted: 05/25/2019] [Indexed: 12/18/2022] Open
Abstract
The formation of the nuclear envelope and the subsequent compartmentalization of the genome is a defining feature of eukaryotes. Traditionally, the nuclear envelope was purely viewed as a physical barrier to preserve genetic material in eukaryotic cells. However, in the last few decades, it has been revealed to be a critical cellular component in controlling gene expression and has been implicated in several human diseases. In cancer, the relevance of the cell nucleus was first reported in the mid-1800s when an altered nuclear morphology was observed in tumor cells. This review aims to give a current and comprehensive view of the role of the nuclear envelope on cancer first by recapitulating the changes of the nuclear envelope during cell division, second, by reviewing the role of the nuclear envelope in cell cycle regulation, signaling, and the regulation of the genome, and finally, by addressing the nuclear envelope link to cell migration and metastasis and its use in cancer prognosis.
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Affiliation(s)
- Maria Alvarado-Kristensson
- Molecular Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, 20502 Malmö, Sweden.
| | - Catalina Ana Rosselló
- Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, 07121 Palma de Mallorca, Spain.
- Lipopharma Therapeutics, Isaac Newton, 07121 Palma de Mallorca, Spain.
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29
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Mullan PB, Bingham V, Haddock P, Irwin GW, Kay E, McQuaid S, Buckley NE. NUP98 - a novel predictor of response to anthracycline-based chemotherapy in triple negative breast cancer. BMC Cancer 2019; 19:236. [PMID: 30935371 PMCID: PMC6444590 DOI: 10.1186/s12885-019-5407-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 02/25/2019] [Indexed: 12/31/2022] Open
Abstract
Background Triple Negative breast cancer (TNBC) is a poor outcome subgroup of breast cancer defined based on the absence of expression of ERα and PR and HER2 amplification. These hard to treat cancers lack targeted treatment options and are therefore treated with a standard of care (SoC) generic cocktail of DNA damaging chemotherapy, with a wide range of clinical responses. While a subset of TNBC patients respond very well to this treatment, others receive no clinical benefit and die from their disease within a short time period. We currently lack biomarkers to prospectively identify patients likely to relapse and we lack alternate treatment options. Methods NUP98 protein expression was investigated in patient samples using two independent tissue microarrays (TMAs), as well as a normal breast TMA. Correlation with pathological response to various chemotherapy regimens was investigated. Results We have shown that high NUP98 is significantly associated with poor outcome in TNBC patient samples both by gene expression and IHC-based protein analysis. While trends linking NUP98 expression with poorer outcomes were observed in breast cancer overall (and more specifically in the LuminalB Her2- subgroup), significant correlations were observed in TNBC. This appeared to be specific to anthracycline based regimens as the association between NUP98 and response was not observed in patients treated with taxane-based chemotherapy. Conclusions We have identified a novel biomarker, NUP98, that can predict response to anthracycline based chemotherapy in TNBC. The ability to prospectively identify patients who are less likely to respond to SoC chemotherapy is a vital step in improving the overall survival of these patients. Electronic supplementary material The online version of this article (10.1186/s12885-019-5407-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Paul B Mullan
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland
| | - Victoria Bingham
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland
| | - Paula Haddock
- School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, Northern Ireland
| | - Gareth W Irwin
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland.,Nightingale Breast Centre, Wythenshawe Hospital, Manchester University Foundation Trust, Manchester, UK
| | - Elaine Kay
- Department of Surgery, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Stephen McQuaid
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland
| | - Niamh E Buckley
- School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, Northern Ireland.
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30
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Abstract
The nuclear pore complex (NPC) serves as the sole bidirectional gateway of macromolecules in and out of the nucleus. Owing to its size and complexity (∼1,000 protein subunits, ∼110 MDa in humans), the NPC has remained one of the foremost challenges for structure determination. Structural studies have now provided atomic-resolution crystal structures of most nucleoporins. The acquisition of these structures, combined with biochemical reconstitution experiments, cross-linking mass spectrometry, and cryo-electron tomography, has facilitated the determination of the near-atomic overall architecture of the symmetric core of the human, fungal, and algal NPCs. Here, we discuss the insights gained from these new advances and outstanding issues regarding NPC structure and function. The powerful combination of bottom-up and top-down approaches toward determining the structure of the NPC offers a paradigm for uncovering the architectures of other complex biological machines to near-atomic resolution.
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Affiliation(s)
- Daniel H Lin
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA;
| | - André Hoelz
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA;
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31
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Oh JH, Lee JY, Yu S, Cho Y, Hur S, Nam KT, Kim MH. RAE1 mediated ZEB1 expression promotes epithelial-mesenchymal transition in breast cancer. Sci Rep 2019; 9:2977. [PMID: 30814639 PMCID: PMC6393568 DOI: 10.1038/s41598-019-39574-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 01/24/2019] [Indexed: 12/21/2022] Open
Abstract
Breast cancer metastasis accounts for most of the deaths from breast cancer. Since epithelial-mesenchymal transition (EMT) plays an important role in promoting metastasis of cancer, many mechanisms regarding EMT have been studied. We previously showed that Ribonucleic acid export 1 (RAE1) is dysregulated in breast cancer and its overexpression leads to aggressive breast cancer phenotypes by inducing EMT. Here, we evaluated the functional capacity of RAE1 in breast cancer metastasis by using a three-dimensional (3D) culture system and xenograft models. Furthermore, to investigate the mechanisms of RAE1-driven EMT, in vitro studies were carried out. The induction of EMT with RAE1-overexpression was confirmed under the 3D culture system and in vivo system. Importantly, RAE1 mediates upregulation of an EMT marker ZEB1, by binding to the promoter region of ZEB1. Knockdown of ZEB1 in RAE1-overexpressing cells suppressed invasive and migratory behaviors, accompanied by an increase in epithelial and a decrease in mesenchymal markers. Taken together, these data demonstrate that RAE1 contributes to breast cancer metastasis by regulating a key EMT-inducing factor ZEB1 expression, suggesting its potential as a therapeutic target.
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Affiliation(s)
- Ji Hoon Oh
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul, 03722, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Ji-Yeon Lee
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Sungsook Yu
- Severance Biomedical Science Institute and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Yejin Cho
- Severance Biomedical Science Institute and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Sumin Hur
- Severance Biomedical Science Institute and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Ki Taek Nam
- Severance Biomedical Science Institute and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Korea.
| | - Myoung Hee Kim
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul, 03722, Korea.
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Korea.
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32
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Kassianidou E, Kalita J, Lim RYH. The role of nucleocytoplasmic transport in mechanotransduction. Exp Cell Res 2019; 377:86-93. [PMID: 30768931 DOI: 10.1016/j.yexcr.2019.02.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 02/10/2019] [Accepted: 02/12/2019] [Indexed: 12/12/2022]
Abstract
Cells integrate mechanical and biochemical signals via a process called mechanotransduction to generate essential gene expression patterns in space and time. This is vital for cell migration and proliferation as well as tissue morphogenesis and remodeling. While the force-sensing and force-transducing mechanisms are generally known, it remains unclear how mechanoresponsive transcription factors (TFs) are selectively translocated into the nucleus upon force activation. Such TFs include Yes-Associated Protein (YAP), Myocardin Related Transcription Factors (MRTFs), Hypoxia Induced Factors (HIFs) and others. Here, we discuss how the nucleocytoplasmic transport machinery intersects with mechanoresponsive TFs to facilitate their selective transport through nuclear pore complexes.
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Affiliation(s)
- Elena Kassianidou
- Biozentrum and the Swiss Nanoscience Institute, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland
| | - Joanna Kalita
- Biozentrum and the Swiss Nanoscience Institute, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland
| | - Roderick Y H Lim
- Biozentrum and the Swiss Nanoscience Institute, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
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33
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Culjkovic-Kraljacic B, Borden KLB. The Impact of Post-transcriptional Control: Better Living Through RNA Regulons. Front Genet 2018; 9:512. [PMID: 30455716 PMCID: PMC6230556 DOI: 10.3389/fgene.2018.00512] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 10/12/2018] [Indexed: 12/26/2022] Open
Abstract
Traditionally, cancer is viewed as a disease driven by genetic mutations and/or epigenetic and transcriptional dysregulation. While these are undoubtedly important drivers, many recent studies highlight the disconnect between the proteome and the genome or transcriptome. At least in part, this disconnect arises as a result of dysregulated RNA metabolism which underpins the altered proteomic landscape observed. Thus, it is important to understand the basic mechanisms governing post-transcriptional control and how these processes can be co-opted to drive cancer cell phenotypes. In some cases, groups of mRNAs that encode protein involved in specific oncogenic processes can be co-regulated at multiple processing levels in order to turn on entire biochemical pathways. Indeed, the RNA regulon model was postulated as a means to understand how cells coordinately regulate transcripts encoding proteins in the same biochemical pathways. In this review, we describe some of the basic mRNA processes that are dysregulated in cancer and the biological impact this has on the cell. This dysregulation can affect networks of RNAs simultaneously thereby underpinning the oncogenic phenotypes observed.
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Affiliation(s)
- Biljana Culjkovic-Kraljacic
- Institute for Research in Immunology and Cancer, Department of Pathology and Cell Biology, University of Montreal, Montreal, QC, Canada
| | - Katherine L B Borden
- Institute for Research in Immunology and Cancer, Department of Pathology and Cell Biology, University of Montreal, Montreal, QC, Canada
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Kato M, McKnight SL. A Solid-State Conceptualization of Information Transfer from Gene to Message to Protein. Annu Rev Biochem 2018; 87:351-390. [DOI: 10.1146/annurev-biochem-061516-044700] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In this review, we describe speculative ideas and early stage research concerning the flow of genetic information from the nuclear residence of genes to the disparate, cytoplasmic sites of protein synthesis. We propose that this process of information transfer is meticulously guided by transient structures formed from protein segments of low sequence complexity/intrinsic disorder. These low complexity domains are ubiquitously associated with regulatory proteins that control gene expression and RNA biogenesis, but they are also found in the central channel of nuclear pores, the nexus points of intermediate filament assembly, and the locations of action of other well-studied cellular proteins and pathways. Upon being organized into localized cellular positions via mechanisms utilizing properly folded protein domains, thereby facilitating elevated local concentration, certain low complexity domains adopt cross-β interactions that are both structurally specific and labile to disassembly. These weakly tethered assemblies, we propose, are built to relay the passage of genetic information from one site to another within a cell, ensuring that the process is of extreme fidelity.
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Affiliation(s)
- Masato Kato
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9152, USA
| | - Steven L. McKnight
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9152, USA
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35
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Ibata S, Kobune M, Kikuchi S, Yoshida M, Miura S, Horiguchi H, Murase K, Iyama S, Takada K, Miyanishi K, Kato J. High expression of nucleoporin 133 mRNA in bone marrow CD138+ cells is a poor prognostic factor in multiple myeloma. Oncotarget 2018; 9:25127-25135. [PMID: 29861858 PMCID: PMC5982762 DOI: 10.18632/oncotarget.25350] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 04/24/2018] [Indexed: 12/13/2022] Open
Abstract
Recent advances in plasma cell biology and molecularly-targeted therapy enable us to employ various types of drugs including immunomodulatory drugs, proteasome inhibitors, and immunotherapy. However, the optimal therapeutic strategies to introduce these drugs for heterogeneous patients with multiple myeloma (MM) have not yet been clarified. In the present study, we attempted to identify a new factor indicating poor prognosis in CD138+ myeloma cells using accumulated Gene Expression Omnibus (GEO) datasets from studies of MM and to assess the relationship between gene expression and survival using MAQC-II Project Myeloma (GSE24080). Five GEO datasets (GSE5900, GSE58133, GSE68871, GSE57317 and GSE16791) which were analyzed by the same microarray platform (GLP570) were combined into one MM database including various types of MM. However, we found that gene expression levels were quite heterogeneous. Hence, we focused on the differentially-expressed genes (DEGs) between newly-diagnosed MM and relapsed/refractory MM and found that the expression levels of more than 20 genes changed two-fold or more. Additionally, pathway analysis indicated that six pathways including Hippo signaling were significantly enriched. Then, we applied all DEGs and genes associated with core enrichment for GSE24080 to evaluate their involvement in disease prognosis. We found that nucleoporin 133 (NUP133) is an independent poor prognostic factor by Cox proportional hazard analysis. These results suggested that high expression of NUP133 could be useful when choosing the appropriate MM therapy and may be a new target of MM therapy.
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Affiliation(s)
- Soushi Ibata
- Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masayoshi Kobune
- Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shohei Kikuchi
- Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiro Yoshida
- Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shogo Miura
- Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroto Horiguchi
- Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kazuyuki Murase
- Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Satoshi Iyama
- Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kohichi Takada
- Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Makise M, Nakamura H, Kuniyasu A. The role of vimentin in the tumor marker Nup88-dependent multinucleated phenotype. BMC Cancer 2018; 18:519. [PMID: 29724197 PMCID: PMC5934895 DOI: 10.1186/s12885-018-4454-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 04/30/2018] [Indexed: 12/31/2022] Open
Abstract
Background Nucleoporin Nup88, a component of nuclear pore complexes, is known to be overexpressed in several types of tumor tissue. The overexpression of Nup88 has been reported to promote the early step of tumorigenesis by inducing multinuclei in both HeLa cells and a mouse model. However, the molecular basis of how Nup88 leads to a multinucleated phenotype remains unclear because of a lack of information concerning its binding partners. In this study, we characterize a novel interaction between Nup88 and vimentin. We also examine the involvement of vimentin in the Nup88-dependent multinucleated phenotype. Methods Cells overexpressing tagged versions of Nup88, vimentin and their truncations were used in this study. Coprecipitation and GST-pulldown assays were carried out to analyze protein-protein interactions. Vimentin knockdown by siRNA was performed to examine the functional role of the Nup88-vimentin interaction in cells. The phosphorylation status of vimentin was analyzed by immunoblotting using an antibody specific for its phosphorylation site. Results Vimentin was identified as a Nup88 interacting partner, although it did not bind to other nucleoporins, such as Nup50, Nup214, and Nup358, in HeLa cell lysates. The N-terminal 541 amino acid residues of Nup88 was found to be responsible for its interaction with vimentin. Recombinant GST-tagged Nup88 bound to recombinant vimentin in a GST-pulldown assay. Although overexpression of Nup88 in HeLa cells was observed mainly at the nuclear rim and in the cytoplasm, colocalization with vimentin was only partially detected at or around the nuclear rim. Disruption of the Nup88-vimentin interaction by vimentin specific siRNA transfection suppressed the Nup88-dependent multinucleated phenotype. An excess amount of Nup88 in cell lysates inhibited the dephosphorylation of a serine residue (Ser83) within the vimentin N-terminal region even in the absence and presence of an exogenous phosphatase. The N-terminal 96 amino acid residues of vimentin interacted with both full-length and the N-terminal 541 residues of Nup88. Conclusions Nup88 can affect the phosphorylation status of vimentin, which may contribute to the Nup88-dependent multinucleated phenotype through changing the organization of vimentin.
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Affiliation(s)
- Masaki Makise
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto, 860-0082, Japan.
| | - Hideaki Nakamura
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto, 860-0082, Japan
| | - Akihiko Kuniyasu
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto, 860-0082, Japan
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Brady GF, Kwan R, Cunha JB, Elenbaas JS, Omary MB. Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease. Gastroenterology 2018; 154:1602-1619.e1. [PMID: 29549040 PMCID: PMC6038707 DOI: 10.1053/j.gastro.2018.03.026] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 03/04/2018] [Accepted: 03/06/2018] [Indexed: 02/07/2023]
Abstract
The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and integral inner nuclear membrane proteins, providing links among the genome, nucleoskeleton, and cytoskeleton. In the 1990s, mutations in EMD and LMNA were linked to Emery-Dreifuss muscular dystrophy. Since then, the number of diseases attributed to nuclear lamina defects, including laminopathies and other disorders, has increased to include more than 20 distinct genetic syndromes. Studies of patients and mouse genetic models have pointed to important roles for lamins and their associated proteins in the function of gastrointestinal organs, including liver and pancreas. We review the interactions and functions of the lamina in relation to the nuclear envelope and genome, the ways in which its dysfunction is thought to contribute to human disease, and possible avenues for targeted therapies.
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Affiliation(s)
- Graham F. Brady
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan,Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan,To whom correspondence should be addressed: University of Michigan Medical School, Division of Gastroenterology, Department of Internal Medicine, 1137 Catherine St., Ann Arbor, MI 48109-5622.
| | - Raymond Kwan
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Juliana Bragazzi Cunha
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Jared S. Elenbaas
- Medical Scientist Training Program, Washington University, St Louis, Missouri
| | - M. Bishr Omary
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan,Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan,Ǻbo Akademi University, Turku, Finland
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Hautbergue GM. RNA Nuclear Export: From Neurological Disorders to Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1007:89-109. [PMID: 28840554 DOI: 10.1007/978-3-319-60733-7_6] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The presence of a nuclear envelope, also known as nuclear membrane, defines the structural framework of all eukaryotic cells by separating the nucleus, which contains the genetic material, from the cytoplasm where the synthesis of proteins takes place. Translation of proteins in Eukaryotes is thus dependent on the active transport of DNA-encoded RNA molecules through pores embedded within the nuclear membrane. Several mechanisms are involved in this process generally referred to as RNA nuclear export or nucleocytoplasmic transport of RNA. The regulated expression of genes requires the nuclear export of protein-coding messenger RNA molecules (mRNAs) as well as non-coding RNAs (ncRNAs) together with proteins and pre-assembled ribosomal subunits. The nuclear export of mRNAs is intrinsically linked to the co-transcriptional processing of nascent transcripts synthesized by the RNA polymerase II. This functional coupling is essential for the survival of cells allowing for timely nuclear export of fully processed transcripts, which could otherwise cause the translation of abnormal proteins such as the polymeric repeat proteins produced in some neurodegenerative diseases. Alterations of the mRNA nuclear export pathways can also lead to genome instability and to various forms of cancer. This chapter will describe the molecular mechanisms driving the nuclear export of RNAs with a particular emphasis on mRNAs. It will also review their known alterations in neurological disorders and cancer, and the recent opportunities they offer for the potential development of novel therapeutic strategies.
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Affiliation(s)
- Guillaume M Hautbergue
- RNA Biology Laboratory, Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
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Nader JS, Abadie J, Deshayes S, Boissard A, Blandin S, Blanquart C, Boisgerault N, Coqueret O, Guette C, Grégoire M, Pouliquen DL. Characterization of increasing stages of invasiveness identifies stromal/cancer cell crosstalk in rat models of mesothelioma. Oncotarget 2018; 9:16311-16329. [PMID: 29662647 PMCID: PMC5893242 DOI: 10.18632/oncotarget.24632] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 02/25/2018] [Indexed: 12/11/2022] Open
Abstract
Sarcomatoid mesothelioma (SM) is a devastating cancer associated with one of the poorest outcome. Therefore, representative preclinical models reproducing different tumor microenvironments (TME) observed in patients would open up new prospects for the identification of markers and evaluation of innovative therapies. Histological analyses of four original models of rat SM revealed their increasing infiltrative and metastatic potential were associated with differences in Ki67 index, blood-vessel density, and T-lymphocyte and macrophage infiltration. In comparison with the noninvasive tumor M5-T2, proteomic analysis demonstrated the three invasive tumors F4-T2, F5-T1 and M5-T1 shared in common a very significant increase in the abundance of the multifunctional proteins galectin-3, prohibitin and annexin A5, and a decrease in proteins involved in cell adhesion, tumor suppression, or epithelial differentiation. The increased metastatic potential of the F5-T1 tumor, relative to F4-T2, was associated with an increased macrophage vs T-cell infiltrate, changes in the levels of expression of a panel of cytokine genes, an increased content of proteins involved in chromatin organization, ribosome structure, splicing, or presenting anti-adhesive properties, and a decreased content of proteins involved in protection against oxidative stress, normoxia and intracellular trafficking. The most invasive tumor, M5-T1, was characterized by a pattern of specific phenotypic and molecular features affecting the presentation of MHC class I-mediated antigens and immune cell infiltration, or involved in the reorganization of the cytoskeleton and composition of the extracellular matrix. These four preclinical models and data represent a new resource available to the cancer research community to catalyze further investigations on invasiveness.
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Affiliation(s)
- Joëlle S. Nader
- CRCINA, INSERM, Université d’Angers, Université de Nantes, Nantes, France
| | - Jérôme Abadie
- CRCINA, INSERM, Université d’Angers, Université de Nantes, Nantes, France
- ONIRIS, Nantes, France
| | - Sophie Deshayes
- CRCINA, INSERM, Université d’Angers, Université de Nantes, Nantes, France
| | - Alice Boissard
- CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France
- ICO, Angers, France
| | - Stéphanie Blandin
- Plate-Forme MicroPICell, SFR François Bonamy, Université de Nantes, France
| | | | | | - Olivier Coqueret
- CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France
- ICO, Angers, France
| | - Catherine Guette
- CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France
- ICO, Angers, France
| | - Marc Grégoire
- CRCINA, INSERM, Université d’Angers, Université de Nantes, Nantes, France
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Sump B, Brickner JH. Nup98 regulation of histone methylation promotes normal gene expression and may drive leukemogenesis. Genes Dev 2018; 31:2201-2203. [PMID: 29284709 PMCID: PMC5769765 DOI: 10.1101/gad.310359.117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
This Outlook by Sump and Brickner highlights the work of Franks et al., which provides new mechanistic insight into the molecular basis by which Nup98 promotes gene activation in normal hematopoietic cells and how that process is altered by translocations to cause excess expression of developmental genes in leukemia. Nuclear pore proteins (Nups) interact with chromosomes to regulate gene expression and chromatin structure. A new study by Franks and colleagues (pp. 2222–2234) provides new mechanistic insight into the molecular basis by which Nup98 promotes gene activation in normal hematopoietic cells and how that process is altered by translocations to cause excess expression of developmental genes in leukemia.
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Affiliation(s)
- Bethany Sump
- Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, USA
| | - Jason H Brickner
- Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, USA
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Franks TM, McCloskey A, Shokirev MN, Benner C, Rathore A, Hetzer MW. Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells. Genes Dev 2017; 31:2222-2234. [PMID: 29269482 PMCID: PMC5769767 DOI: 10.1101/gad.306753.117] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 11/21/2017] [Indexed: 12/26/2022]
Abstract
In this study, Franks et al. investigated the mechanisms underlying how Nup98 regulates gene expression. They show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark, and expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at aberrant regions and up-regulation of associated genes due to aberrant Wdr82/Set1A activity. Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML.
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Affiliation(s)
- Tobias M Franks
- Laboratory of Molecular and Cellular Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA
| | - Asako McCloskey
- Laboratory of Molecular and Cellular Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA
| | - Maxim Nikolaievich Shokirev
- The Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California 92037, USA
| | - Chris Benner
- Laboratory of Molecular and Cellular Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA.,Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA
| | - Annie Rathore
- Laboratory of Molecular and Cellular Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA
| | - Martin W Hetzer
- Laboratory of Molecular and Cellular Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA
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Beck M, Schirmacher P, Singer S. Alterations of the nuclear transport system in hepatocellular carcinoma - New basis for therapeutic strategies. J Hepatol 2017; 67:1051-1061. [PMID: 28673770 DOI: 10.1016/j.jhep.2017.06.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 06/20/2017] [Accepted: 06/21/2017] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) is among the most prevalent human malignancies worldwide with rising incidence in industrialised countries, few therapeutic options and poor prognosis. To expand and improve therapeutic strategies, identification of drug targets involved in several liver cancer-related pathways is crucial. Virtually all signal transduction cascades cross the nuclear envelope and therefore require components of the nuclear transport system (NTS), including nuclear transport receptors (e.g. importins and exportins) and the nuclear pore complex. Accordingly, members of the NTS represent promising targets for therapeutic intervention. Selective inhibitors of nuclear export have already entered clinical trials for various malignancies. Herein, we review the current knowledge regarding alterations of the NTS and their potential for targeted therapy in HCC.
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Affiliation(s)
- Martin Beck
- European Molecular Biology Laboratory, Heidelberg, Germany
| | | | - Stephan Singer
- European Molecular Biology Laboratory, Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Germany.
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Zhang J, Zhi C, Zhen F, Yuan X, Jiao C, Zhu H, Zhu H, Feng Y. iTRAQ-Based Quantitative Proteomic Analyses of High Grade Esophageal Squamous Intraepithelial Neoplasia. Proteomics Clin Appl 2017; 11. [PMID: 28816019 DOI: 10.1002/prca.201600167] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 07/18/2017] [Indexed: 01/08/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and is the fourth most lethal cancer in China. Little is known about the proteome of high grade esophageal squamous intraepithelial neoplasia (HGN), which is a premalignant lesion of ESCC. A quantitative proteomic analysis using an isobaric tag for relative and absolute quantification (iTRAQ) approach is used to characterize the protein expression profiles in HGN. Among the 3156 identified proteins, a total of 236 proteins are discovered to be differentially expressed. Compared with paired normal esophageal epithelial tissues, 138 proteins are upregulated and 98 proteins are downregulated in HGN. Bioinformatics analyses are performed according to gene ontology, clusters of orthologous groups, and kyoto encyclopedia of genes and genomes enrichment analyses. Six differentially expressed proteins are chosen and validated by Western blotting. The results of the study increase our understanding of early tumorigenesis during ESCC, and provide insights into the proteome at the initial stages of the disease that can be used to identify potential biomarkers for early diagnosis and for therapeutic targets.
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Affiliation(s)
- Jingjing Zhang
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Jiangning, Nanjing, China.,Department of Prenatal Diagnosis, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Chunchun Zhi
- Department of Anatomy, Nanjing Medical University, Jiangning, Nanjing, China
| | - Fuxi Zhen
- Department of Cardio-thoracic Surgery, First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Xiaoqin Yuan
- Department of Anatomy, Nanjing Medical University, Jiangning, Nanjing, China
| | - Chunhua Jiao
- Department of Gastroenterology, First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Hong Zhu
- Department of Gastroenterology, First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Hui Zhu
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Jiangning, Nanjing, China
| | - Yadong Feng
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, China.,Previously Department of Gastroenterology, First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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Jung HJ. Chemical Proteomic Approaches Targeting Cancer Stem Cells: A Review of Current Literature. Cancer Genomics Proteomics 2017; 14:315-327. [PMID: 28870999 PMCID: PMC5611518 DOI: 10.21873/cgp.20042] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 07/18/2017] [Accepted: 07/20/2017] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) have been proposed as central drivers of tumor initiation, progression, recurrence, and therapeutic resistance. Therefore, identifying stem-like cells within cancers and understanding their properties is crucial for the development of effective anticancer therapies. Recently, chemical proteomics has become a powerful tool to efficiently determine protein networks responsible for CSC pathophysiology and comprehensively elucidate molecular mechanisms of drug action against CSCs. This review provides an overview of major methodologies utilized in chemical proteomic approaches. In addition, recent successful chemical proteomic applications targeting CSCs are highlighted. Future direction of potential CSC research by integrating chemical genomic and proteomic data obtained from a single biological sample of CSCs are also suggested in this review.
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Affiliation(s)
- Hye Jin Jung
- Department of BT-Convergent Pharmaceutical Engineering, Sun Moon University, Asan, Republic of Korea
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Sakuma S, D'Angelo MA. The roles of the nuclear pore complex in cellular dysfunction, aging and disease. Semin Cell Dev Biol 2017; 68:72-84. [PMID: 28506892 DOI: 10.1016/j.semcdb.2017.05.006] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 05/11/2017] [Indexed: 12/19/2022]
Abstract
The study of the Nuclear Pore Complex (NPC), the proteins that compose it (nucleoporins), and the nucleocytoplasmic transport that it controls have revealed an unexpected layer to pathogenic disease onset and progression. Recent advances in the study of the regulation of NPC composition and function suggest that the precise control of this structure is necessary to prevent diseases from arising or progressing. Here we discuss the role of nucleoporins in a diverse set of diseases, many of which directly or indirectly increase in occurrence and severity as we age, and often shorten the human lifespan. NPC biology has been shown to play a direct role in these diseases and therefore in the process of healthy aging.
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Affiliation(s)
- Stephen Sakuma
- Development, Aging and Regeneration Program (DARe), Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Maximiliano A D'Angelo
- Development, Aging and Regeneration Program (DARe), Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
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Toxic PR n poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc Natl Acad Sci U S A 2017; 114:E1111-E1117. [PMID: 28069952 DOI: 10.1073/pnas.1620293114] [Citation(s) in RCA: 174] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The toxic proline:arginine (PRn) poly-dipeptide encoded by the (GGGGCC)n repeat expansion in the C9orf72 form of heritable amyotrophic lateral sclerosis (ALS) binds to the central channel of the nuclear pore and inhibits the movement of macromolecules into and out of the nucleus. The PRn poly-dipeptide binds to polymeric forms of the phenylalanine:glycine (FG) repeat domain, which is shared by several proteins of the nuclear pore complex, including those in the central channel. A method of chemical footprinting was used to characterize labile, cross-β polymers formed from the FG domain of the Nup54 protein. Mutations within the footprinted region of Nup54 polymers blocked both polymerization and binding by the PRn poly-dipeptide. The aliphatic alcohol 1,6-hexanediol melted FG domain polymers in vitro and reversed PRn-mediated enhancement of the nuclear pore permeability barrier. These data suggest that toxicity of the PRn poly-dipeptide results in part from its ability to lock the FG repeats of nuclear pore proteins in the polymerized state. Our study offers a mechanistic interpretation of PRn poly-dipeptide toxicity in the context of a prominent form of ALS.
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Abstract
Knowing the configuration of the nuclear pore is essential for appreciating the underlying mechanisms of nucleo-cytoplasmic communication. Now, Fernandez-Martinez et al. present a high-resolution structure of the cytoplasmic nuclear pore-mRNA export holo-complex, challenging our textbook depiction of this massive membrane-embedded complex.
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Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway. Mol Cell Biol 2016; 36:1820-35. [PMID: 27114368 DOI: 10.1128/mcb.00158-16] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 04/14/2016] [Indexed: 02/07/2023] Open
Abstract
Nuclear-cytoplasmic transport through nuclear pore complexes is mediated by nuclear transport receptors. Previous reports have suggested that aberrant nuclear-cytoplasmic transport due to mutations or overexpression of nuclear pore complexes and nuclear transport receptors is closely linked to diseases. Nup214, a component of nuclear pore complexes, has been found as chimeric fusion proteins in leukemia. Among various Nup214 fusion proteins, SET-Nup214 and DEK-Nup214 have been shown to be engaged in tumorigenesis, but their oncogenic mechanisms remain unclear. In this study, we examined the functions of the Nup214 fusion proteins by focusing on their effects on nuclear-cytoplasmic transport. We found that SET-Nup214 and DEK-Nup214 interact with exportin-1 (XPO1)/CRM1 and nuclear RNA export factor 1 (NXF1)/TAP, which mediate leucine-rich nuclear export signal (NES)-dependent protein export and mRNA export, respectively. SET-Nup214 and DEK-Nup214 decreased the XPO1-mediated nuclear export of NES proteins such as cyclin B and proteins involved in the NF-κB signaling pathway by tethering XPO1 onto nuclear dots where Nup214 fusion proteins are localized. We also demonstrated that SET-Nup214 and DEK-Nup214 expression inhibited NF-κB-mediated transcription by abnormal tethering of the complex containing p65 and its inhibitor, IκB, in the nucleus. These results suggest that SET-Nup214 and DEK-Nup214 perturb the regulation of gene expression through alteration of the nuclear-cytoplasmic transport system.
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Zhu HH, Zhao XS, Qin YZ, Lai YY, Jiang H. B-cell acute lymphoblastic leukemia associated with SET-NUP214 rearrangement: A case report and review of the literature. Oncol Lett 2016; 11:2644-2650. [PMID: 27073532 DOI: 10.3892/ol.2016.4260] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 01/15/2016] [Indexed: 12/24/2022] Open
Abstract
The SET nuclear proto-oncogene (SET)-nucleoporin (NUP)214 fusion gene, which results from cryptic t(9;9)(q34;q34) or del(9)(q34.11q34.13), is a rare genetic event in hematological malignancies. The majority of patients carrying SET-NUP214 experience T-cell acute lymphoblastic leukemia (T-ALL), but rarely experience acute undifferentiated leukemia or acute myeloid leukemia. The current study presents the case of a 19-year-old male patient with B-cell ALL (B-ALL) carrying the SET-NUP214 fusion gene, in addition to an fms-related tyrosine kinase 3-internal tandem duplication mutation and a complex karyotype abnormality. The patient exhibited chemotherapy resistance. To the best of our knowledge, the present study is the first report of a case of B-ALL carrying the SET-NUP214 fusion gene, and provides a review of the literature.
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Affiliation(s)
- Hong-Hu Zhu
- Department of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, P.R. China
| | - Xiao-Su Zhao
- Department of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, P.R. China
| | - Ya-Zhen Qin
- Department of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, P.R. China
| | - Yue-Yun Lai
- Department of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, P.R. China
| | - Hao Jiang
- Department of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, P.R. China
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Oka M, Mura S, Yamada K, Sangel P, Hirata S, Maehara K, Kawakami K, Tachibana T, Ohkawa Y, Kimura H, Yoneda Y. Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes. eLife 2016; 5:e09540. [PMID: 26740045 PMCID: PMC4718815 DOI: 10.7554/elife.09540] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 11/16/2015] [Indexed: 01/14/2023] Open
Abstract
The nucleoporin Nup98 is frequently rearranged to form leukemogenic Nup98-fusion proteins with various partners. However, their function remains largely elusive. Here, we show that Nup98-HoxA9, a fusion between Nup98 and the homeobox transcription factor HoxA9, forms nuclear aggregates that frequently associate with facultative heterochromatin. We demonstrate that stable expression of Nup98-HoxA9 in mouse embryonic stem cells selectively induces the expression of Hox cluster genes. Genome-wide binding site analysis revealed that Nup98-HoxA9 is preferentially targeted and accumulated at Hox cluster regions where the export factor Crm1 is originally prebound. In addition, leptomycin B, an inhibitor of Crm1, disassembled nuclear Nup98-HoxA9 dots, resulting in the loss of chromatin binding of Nup98-HoxA9 and Nup98-HoxA9-mediated activation of Hox genes. Collectively, our results indicate that highly selective targeting of Nup98-fusion proteins to Hox cluster regions via prebound Crm1 induces the formation of higher order chromatin structures that causes aberrant Hox gene regulation.
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Affiliation(s)
- Masahiro Oka
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Sonoko Mura
- Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
| | - Kohji Yamada
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Percival Sangel
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Saki Hirata
- Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan
| | - Kazumitsu Maehara
- Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan
| | - Koichi Kawakami
- Division of Molecular and Developmental Biology, National Institute of Genetics, Shizuoka, Japan
| | - Taro Tachibana
- Department of Bioengineering, Osaka City University, Graduate School of Engineering, Osaka, Japan
| | - Yasuyuki Ohkawa
- Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan
| | - Hiroshi Kimura
- Department of Biological Sciences, Graduate School of Bioscience and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Yoshihiro Yoneda
- Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
- National Institutes of Biomedical Innovation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
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