|
1
|
Poirier A, Utecht T, Villot R, Gélinas Y, Mouchiroud M, Kordahi M, Kolnohuz A, Pasteur C, Roy J, Beaulieu MJ, Orain M, Samson N, Blanchet MR, Joubert P, Laplante M. ZNF768 loss amplifies p53 action and reduces lung tumorigenesis in mice. Oncogene 2025:10.1038/s41388-025-03352-w. [PMID: 40133474 DOI: 10.1038/s41388-025-03352-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 02/17/2025] [Accepted: 03/11/2025] [Indexed: 03/27/2025]
Abstract
Cell proliferation is a fundamental process required for organismal development, growth, and maintenance. Failure to control this process leads to several diseases, including cancer. Zinc finger protein 768 (ZNF768) is an emerging transcription factor that plays key roles in driving proliferation. In addition to controlling a gene network supporting cell division, ZNF768 physically interacts and inhibits the activity of the tumor suppressor p53. Although the importance of ZNF768 in promoting cell proliferation has been well demonstrated in vitro, the physiological and pathological roles of ZNF768 in vivo are still unknown. Here, we report the generation and characterization of a ZNF768 null mouse model. ZNF768 null mice are viable but show a growth defect early in life. Mouse embryonic fibroblasts (MEFs) isolated from ZNF768 null embryos exhibit higher p53 levels, premature senescence, and higher sensitivity to genotoxic stress. In line with these findings, ZNF768 null mice showed increased radiosensitivity. This effect was associated not only with higher expression of a subset of p53 target genes, but also with alterations in genes regulating transmembrane receptor signaling, cell adhesion, and growth. Because ZNF768 levels are elevated in tumors, we tested the impact of ZNF768 loss on cancer development in mice. Here, we show that ZNF768 deletion was sufficient to repress lung tumor development in a KRASG12D-induced cancer mouse model. Overall, our findings establish ZNF768 as an important protein controlling cell proliferation that could potentially be targeted to reduce tumorigenesis.
Collapse
Affiliation(s)
- Audrey Poirier
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
- Centre de recherche sur le cancer de l'Université Laval, Université Laval, Québec, QC, Canada
| | - Timon Utecht
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
| | - Romain Villot
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
| | - Yves Gélinas
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
| | - Mathilde Mouchiroud
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
| | - Manal Kordahi
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
| | - Alona Kolnohuz
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
- Centre de recherche sur le cancer de l'Université Laval, Université Laval, Québec, QC, Canada
| | - Coline Pasteur
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
| | - Joanny Roy
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
| | - Marie-Josée Beaulieu
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
| | - Michèle Orain
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
| | - Nolwenn Samson
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
| | - Marie-Renée Blanchet
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
- Faculté de médecine, Université Laval, Québec, QC, Canada
| | - Philippe Joubert
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada
- Centre de recherche sur le cancer de l'Université Laval, Université Laval, Québec, QC, Canada
- Faculté de médecine, Université Laval, Québec, QC, Canada
| | - Mathieu Laplante
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, QC, Canada.
- Centre de recherche sur le cancer de l'Université Laval, Université Laval, Québec, QC, Canada.
- Faculté de médecine, Université Laval, Québec, QC, Canada.
| |
Collapse
|
|
2
|
Rahmé R, Resnick-Silverman L, Anguiano V, Campbell MJ, Fenaux P, Manfredi JJ. Mutant p53 regulates a distinct gene set by a mode of genome occupancy that is shared with wild type. EMBO Rep 2025; 26:1315-1343. [PMID: 39875582 PMCID: PMC11893899 DOI: 10.1038/s44319-025-00375-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: 07/28/2023] [Revised: 01/05/2025] [Accepted: 01/14/2025] [Indexed: 01/30/2025] Open
Abstract
To directly examine the interplay between mutant p53 or Mdm2 and wild type p53 in gene occupancy and expression, an integrated RNA-seq and ChIP-seq analysis was performed in vivo using isogenically matched mouse strains. Response to radiation was used as an endpoint to place findings in a biologically relevant context. Unexpectedly, mutant p53 and Mdm2 only inhibit a subset of wild type p53-mediated gene expression. In contrast to a dominant-negative or inhibitory role, the presence of either mutant p53 or Mdm2 actually enhances the occupancy of wild type p53 on many canonical targets. The C-terminal 19 amino acids of wild type p53 suppress the p53 response allowing for survival at sublethal doses of radiation. Further, the p53 mutant 172H is shown to occupy genes and regulate their expression via non-canonical means that are shared with wild type p53. This results in the heterozygous 172H/+ genotype having an expanded transcriptome compared to wild type p53 + /+.
Collapse
Affiliation(s)
- Ramy Rahmé
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Institut de Recherche Saint Louis (IRSL), INSERM U1131, Université de Paris, Paris, France
- Ecole Doctorale Hématologie-Oncogenèse-Biothérapies, Université de Paris, Paris, France
| | - Lois Resnick-Silverman
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Vincent Anguiano
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | | | - Pierre Fenaux
- Institut de Recherche Saint Louis (IRSL), INSERM U1131, Université de Paris, Paris, France
- Service Hématologie Seniors, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France
| | - James J Manfredi
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| |
Collapse
|
|
3
|
Peuget S, Zhou X, Selivanova G. Translating p53-based therapies for cancer into the clinic. Nat Rev Cancer 2024; 24:192-215. [PMID: 38287107 DOI: 10.1038/s41568-023-00658-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/12/2023] [Indexed: 01/31/2024]
Abstract
Inactivation of the most important tumour suppressor gene TP53 occurs in most, if not all, human cancers. Loss of functional wild-type p53 is achieved via two main mechanisms: mutation of the gene leading to an absence of tumour suppressor activity and, in some cases, gain-of-oncogenic function; or inhibition of the wild-type p53 protein mediated by overexpression of its negative regulators MDM2 and MDMX. Because of its high potency as a tumour suppressor and the dependence of at least some established tumours on its inactivation, p53 appears to be a highly attractive target for the development of new anticancer drugs. However, p53 is a transcription factor and therefore has long been considered undruggable. Nevertheless, several innovative strategies have been pursued for targeting dysfunctional p53 for cancer treatment. In mutant p53-expressing tumours, the predominant strategy is to restore tumour suppressor function with compounds acting either in a generic manner or otherwise selective for one or a few specific p53 mutations. In addition, approaches to deplete mutant p53 or to target vulnerabilities created by mutant p53 expression are currently under development. In wild-type p53 tumours, the major approach is to protect p53 from the actions of MDM2 and MDMX by targeting these negative regulators with inhibitors. Although the results of at least some clinical trials of MDM2 inhibitors and mutant p53-restoring compounds are promising, none of the agents has yet been approved by the FDA. Alternative strategies, based on a better understanding of p53 biology, the mechanisms of action of compounds and treatment regimens as well as the development of new technologies are gaining interest, such as proteolysis-targeting chimeras for MDM2 degradation. Other approaches are taking advantage of the progress made in immune-based therapies for cancer. In this Review, we present these ongoing clinical trials and emerging approaches to re-evaluate the current state of knowledge of p53-based therapies for cancer.
Collapse
Affiliation(s)
- Sylvain Peuget
- Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Xiaolei Zhou
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Institute of Materials Science and Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Galina Selivanova
- Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
| |
Collapse
|
|
4
|
Alvandi M, Javid RN, Shaghaghi Z, Farzipour S, Nosrati S. An In-depth Analysis of the Adverse Effects of Ionizing Radiation Exposure on Cardiac Catheterization Staffs. Curr Radiopharm 2024; 17:219-228. [PMID: 38314600 DOI: 10.2174/0118744710283181231229112417] [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: 09/19/2023] [Revised: 10/30/2023] [Accepted: 11/08/2023] [Indexed: 02/06/2024]
Abstract
Diagnostic and interventional angiograms are instrumental in the multidisciplinary approach to CAD management, enabling accurate diagnosis and effective targeted treatments that significantly enhance patient care and cardiovascular outcomes. However, cath lab staff, including interventional cardiologists, is consistently exposed to ionizing radiation, which poses inherent health risks. Radiation exposure in the cath lab primarily results from the use of fluoroscopy and cineangiography during diagnostic and interventional procedures. Understanding these risks and implementing effective radiation protection measurements are imperative to ensure the well-being of healthcare professionals while delivering high-quality cardiac care. Prolonged and repeated exposure can lead to both deterministic and stochastic effects. Deterministic effects, such as skin erythema and tissue damage, are more likely to occur at high radiation doses. Interventional cardiologists and staff may experience these effects when safety measures are not rigorously followed. In fact, while ionizing radiation is essential in the practice of radiation cardiology ward, cath lab staff faces inherent risks from radiation exposure. Stochastic effects, on the other hand, are characterized by a probabilistic relationship between radiation exposure and the likelihood of harm. These effects include the increased risk of cancer, particularly for those with long-term exposure. Interventional cardiologists, due to their frequent presence in the cath lab, face a higher lifetime cumulative radiation dose, potentially elevating their cancer risk. Protective measures, including the use of lead aprons, thyroid shields, and radiation monitoring devices, play a crucial role in reducing radiation exposure for cath lab personnel. Adherence to strict dose optimization protocols, such as minimizing fluoroscopy time and maximizing distance from the radiation source, is also essential in mitigating these risks. Ongoing research and advancements in radiation safety technology are essential in further for minimizing the adverse effects of ionizing radiation in the cath lab.
Collapse
Affiliation(s)
- Maryam Alvandi
- Cardiovascular Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Nuclear Medicine and Molecular Imaging, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Zahra Shaghaghi
- Cancer Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Soghra Farzipour
- Department of Cardiology, Cardiovascular Diseases Research Center, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Guilan, Iran
| | - Sahar Nosrati
- Institute of Nuclear Chemistry and Technology, Dorodna 16 Str, 03-195, Warsaw, Poland
| |
Collapse
|
|
5
|
Ribeiro JH, Altinisik N, Rajan N, Verslegers M, Baatout S, Gopalakrishnan J, Quintens R. DNA damage and repair: underlying mechanisms leading to microcephaly. Front Cell Dev Biol 2023; 11:1268565. [PMID: 37881689 PMCID: PMC10597653 DOI: 10.3389/fcell.2023.1268565] [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: 07/28/2023] [Accepted: 09/25/2023] [Indexed: 10/27/2023] Open
Abstract
DNA-damaging agents and endogenous DNA damage constantly harm genome integrity. Under genotoxic stress conditions, the DNA damage response (DDR) machinery is crucial in repairing lesions and preventing mutations in the basic structure of the DNA. Different repair pathways are implicated in the resolution of such lesions. For instance, the non-homologous DNA end joining and homologous recombination pathways are central cellular mechanisms by which eukaryotic cells maintain genome integrity. However, defects in these pathways are often associated with neurological disorders, indicating the pivotal role of DDR in normal brain development. Moreover, the brain is the most sensitive organ affected by DNA-damaging agents compared to other tissues during the prenatal period. The accumulation of lesions is believed to induce cell death, reduce proliferation and premature differentiation of neural stem and progenitor cells, and reduce brain size (microcephaly). Microcephaly is mainly caused by genetic mutations, especially genes encoding proteins involved in centrosomes and DNA repair pathways. However, it can also be induced by exposure to ionizing radiation and intrauterine infections such as the Zika virus. This review explains mammalian cortical development and the major DNA repair pathways that may lead to microcephaly when impaired. Next, we discuss the mechanisms and possible exposures leading to DNA damage and p53 hyperactivation culminating in microcephaly.
Collapse
Affiliation(s)
- Jessica Honorato Ribeiro
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
- Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium
| | - Nazlican Altinisik
- Laboratory for Centrosome and Cytoskeleton Biology, Institute of Human Genetics, University Hospital, Heinrich-Heine-Universität, Düsseldorf, Germany
| | - Nicholas Rajan
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Mieke Verslegers
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Sarah Baatout
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
- Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium
| | - Jay Gopalakrishnan
- Laboratory for Centrosome and Cytoskeleton Biology, Institute of Human Genetics, University Hospital, Heinrich-Heine-Universität, Düsseldorf, Germany
| | - Roel Quintens
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| |
Collapse
|
|
6
|
Ju Z, Lei M, Xuan L, Luo J, Zhou M, Wang Y, Shen L, Skonieczna M, Ivanov DS, M H Zakaly H, Markovic V, Zhou P, Huang R. P53-response circRNA_0006420 aggravates lung cancer radiotherapy resistance by promoting formation of HUR/PTBP1 complex. J Adv Res 2023:S2090-1232(23)00203-5. [PMID: 37541584 DOI: 10.1016/j.jare.2023.07.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 07/18/2023] [Accepted: 07/26/2023] [Indexed: 08/06/2023] Open
Abstract
BACKGROUND p53 wild-type lung cancer cells can develop radiation resistance. Circular RNA (circRNA) consists of a family of transcripts with exclusive structures. circRNA is critical in tumorigenesis and is a potential biomarker or therapeutic target. It is uncertain how circRNA expression and functions are regulated post-radiation in p53 wild-type cancer cells. METHODS A549 or H1299 cells were divided into p53-wt and p53-KO groups by CRISPR/Cas9; both groups were subjected to 4Gy ionizing radiation (IR: p53-wt-IR and p53-KO-IR). RNA-seq, CCK8, cell cycle, and other functional and mechanism experiments were performed in vivo. p53 gene knockout mice were generated to test the cell results in vitro. RESULTS circRNAs were found in differential groups. circRNA_0006420 (IRSense) was upregulated in p53-wt cells but had the same expression level as p53-KO cells after radiation, indicating that p53 silencing prevents its upregulation after IR. In the presence of p53, upregulated IRSense post-radiation induces G2/M arrest by regulating DNA damage repair (DDR) pathway-related proteins. Meanwhile, upregulated IRSense post-radiation aggravates the radiation-induced epithelial-mesenchymal transition (EMT). Interestingly, in the presence of p53, it promotes IRSense/HUR/PTBP1 complex formation resulting in the promotion of the radiation-induced EMT. Moreover, c-Jun regulates the upregulation of p53 transcription after radiation treatment. For these lung cancer cells with p53, upregulated IRSense aggravates lung cancer cell proliferation and increases radiation resistance by interacting with HUR (ElAV-like protein 1) and PTBP1 (polypyrimidine tract-binding protein 1) in the nucleus. CONCLUSIONS Lung cancer cells retaining p53 may upregulate circRNA_0006420 (IRSense) expression post radiation to form an IRSense/HUR/PTBP1 complex leading to radiotherapy resistance. This study furthers our understanding of the roles of circRNA in regulating the effect of radiotherapy and provides novel therapeutic avenues for effective clinical lung cancer therapies.
Collapse
Affiliation(s)
- Zhao Ju
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Mingjun Lei
- Department of Oncology, Xiangya Hospital, Central South University.
| | - Lihui Xuan
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, 410078, China.
| | - Jinhua Luo
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, 410078, China.
| | - Meiling Zhou
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, 410078, China.
| | - Yin Wang
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, 410078, China.
| | - Liangfang Shen
- Department of Oncology, Xiangya Hospital, Central South University.
| | - Magdalena Skonieczna
- Department of Systems Biology and Engineering, Silesian University of Technology, Institute of Automatic Control, Akademicka 16, Gliwice 44-100, Poland, Biotechnology Centre, Silesian University of Technology, Krzywoustego 8, Gliwice 44-100, Poland.
| | - Dmitry S Ivanov
- Quantum Electronics Division, Lebedev Physical Institute, 119991 Moscow, Russia.
| | - Hesham M H Zakaly
- Experimental Physics Department, Institute of Physics and Technology, Ural Federal University, Ekaterinburg, Russia.
| | - Vladimir Markovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac.
| | - Pingkun Zhou
- Beijing Institute of Radiation medicine, Beijing, China.
| | - Ruixue Huang
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, 410078, China.
| |
Collapse
|
|
7
|
Resnick-Silverman L, Zhou R, Campbell MJ, Leibling I, Parsons R, Manfredi JJ. In vivo RNA-seq and ChIP-seq analyses show an obligatory role for the C terminus of p53 in conferring tissue-specific radiation sensitivity. Cell Rep 2023; 42:112216. [PMID: 36924496 DOI: 10.1016/j.celrep.2023.112216] [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: 03/18/2022] [Revised: 09/27/2022] [Accepted: 02/17/2023] [Indexed: 03/17/2023] Open
Abstract
Thymus and spleen, in contrast to liver, are radiosensitive tissues in which p53-dependent apoptosis is triggered after whole-body radiation in vivo. Combined RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses of radiation-treated mouse organs identifies both shared and tissue-specific p53 transcriptional responses. As expected, the p53 targets shared among thymus and spleen are enriched in apoptotic targets. The inability to upregulate these genes in the liver is not due to reduced gene occupancy. Use of an engineered mouse model shows that deletion of the C terminus of p53 can confer radiation-induced expression of p53 apoptotic targets in the liver with concomitant increased cell death. Global RNA-seq analysis reveals that an additional role of the C terminus is also needed for transcriptional activation of liver-specific p53 targets. It is hypothesized that both suppression of apoptotic gene expression combined with enhanced activation of liver-specific targets confers tissue-specific radio-resistance.
Collapse
Affiliation(s)
- Lois Resnick-Silverman
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Royce Zhou
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Moray J Campbell
- Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy at The Ohio State University, Columbus, OH 43210, USA
| | - Ian Leibling
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ramon Parsons
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - James J Manfredi
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| |
Collapse
|
|
8
|
Guan Z, Liang Y, Wang X, Zhu Z, Yang A, Li S, Yu J, Niu B, Wang J. Unraveling the Mechanisms of Clinical Drugs-Induced Neural Tube Defects Based on Network Pharmacology and Molecular Docking Analysis. Neurochem Res 2022; 47:3709-3722. [PMID: 35960485 DOI: 10.1007/s11064-022-03717-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/23/2022] [Accepted: 07/31/2022] [Indexed: 11/30/2022]
Abstract
Chemotherapeutic agents such as methotrexate (MTX), raltitrexed (RTX), 5-fluorouracil (5-FU), hydroxyurea (HU), and retinoic acid (RA), and valproic acid (VPA), an antiepileptic drug, all can cause malformations in the developing central nervous system (CNS), such as neural tube defects (NTDs). However, the common pathogenic mechanisms remain unclear. This study aimed to explore the mechanisms of NTDs caused by MTX, RTX, 5-FU, HU, RA, and VPA (MRFHRV), based on network pharmacology and molecular biology experiments. The MRFHRV targets were integrated with disease targets, to find the potential molecules related to MRFHRV-induced NTDs. Protein-protein interaction analysis and molecular docking were performed to analyze these common targets. Utilizing the kyoto encyclopedia of genes and genomes (KEGG) signaling pathways, we analyzed and searched the possible causative pathogenic mechanisms by crucial targets and the signaling pathway. Results showed that MRFHRV induced NTDs through several key targets (including TP53, MAPK1, HSP90AA1, ESR1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN) and multiple signaling pathways such as PI3K/Akt pathway, suggesting that abnormal proliferation and differentiation could be critical pathogenic contributors in NTDs induced by MRFHRV. These results were further validated by CCK8 assay in mouse embryonic stem cells and GFAP staining in embryonic brain tissue. This study indicated that chemotherapeutic and antiepileptic agents induced NTDs might through predicted targets TP53, MAPK1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN and multiple signaling pathways. More caution was required for the clinical administration for women with childbearing potential and pregnant.
Collapse
Affiliation(s)
- Zhen Guan
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Yingchao Liang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Xiuwei Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Zhiqiang Zhu
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Aiyun Yang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Shen Li
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Jialu Yu
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Bo Niu
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China.
| | - Jianhua Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China.
| |
Collapse
|
|
9
|
Wang Y, Zhang G, Meng Q, Huang S, Guo P, Leng Q, Sun L, Liu G, Huang X, Liu J. Precise tumor immune rewiring via synthetic CRISPRa circuits gated by concurrent gain/loss of transcription factors. Nat Commun 2022; 13:1454. [PMID: 35304449 PMCID: PMC8933567 DOI: 10.1038/s41467-022-29120-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 03/01/2022] [Indexed: 12/14/2022] Open
Abstract
Reinvigoration of antitumor immunity has recently become the central theme for the development of cancer therapies. Nevertheless, the precise delivery of immunotherapeutic activities to the tumors remains challenging. Here, we explore a synthetic gene circuit-based strategy for specific tumor identification, and for subsequently engaging immune activation. By design, these circuits are assembled from two interactive modules, i.e., an oncogenic TF-driven CRISPRa effector, and a corresponding p53-inducible off-switch (NOT gate), which jointly execute an AND-NOT logic for accurate tumor targeting. In particular, two forms of the NOT gate are developed, via the use of an inhibitory sgRNA or an anti-CRISPR protein, with the second form showing a superior performance in gating CRISPRa by p53 loss. Functionally, the optimized AND-NOT logic circuit can empower a highly specific and effective tumor recognition/immune rewiring axis, leading to therapeutic effects in vivo. Taken together, our work presents an adaptable strategy for the development of precisely delivered immunotherapy. “Reinvigoration of antitumor immunity has recently become the central theme for the development of cancer therapies. Here the authors present an adaptable gene circuit to harness the CRISPRa for tumorlocalized immune activation.”
Collapse
Affiliation(s)
- Yafeng Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China.,Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Guiquan Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China
| | - Qingzhou Meng
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 78 Hengzhigang Road, Guangzhou, 510095, China
| | - Shisheng Huang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Panpan Guo
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Qibin Leng
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 78 Hengzhigang Road, Guangzhou, 510095, China
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Geng Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China. .,Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China.
| | - Xingxu Huang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. .,Zhejiang Laboratory, Hangzhou, 311100, China.
| | - Jianghuai Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China. .,Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China.
| |
Collapse
|
|
10
|
Humpton TJ, Hock AK, Kiourtis C, Donatis MD, Fercoq F, Nixon C, Bryson S, Strathdee D, Carlin LM, Bird TG, Blyth K, Vousden KH. A noninvasive iRFP713 p53 reporter reveals dynamic p53 activity in response to irradiation and liver regeneration in vivo. Sci Signal 2022; 15:eabd9099. [PMID: 35133863 PMCID: PMC7612476 DOI: 10.1126/scisignal.abd9099] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Genetically encoded probes are widely used to visualize cellular processes in vitro and in vivo. Although effective in cultured cells, fluorescent protein tags and reporters are suboptimal in vivo because of poor tissue penetration and high background signal. Luciferase reporters offer improved signal-to-noise ratios but require injections of luciferin that can lead to variable responses and that limit the number and timing of data points that can be gathered. Such issues in studying the critical transcription factor p53 have limited insight on its activity in vivo during development and tissue injury responses. Here, by linking the expression of the near-infrared fluorescent protein iRFP713 to a synthetic p53-responsive promoter, we generated a knock-in reporter mouse that enabled noninvasive, longitudinal analysis of p53 activity in vivo in response to various stimuli. In the developing embryo, this model revealed the timing and localization of p53 activation. In adult mice, the model monitored p53 activation in response to irradiation and paracetamol- or CCl4-induced liver regeneration. After irradiation, we observed potent and sustained activation of p53 in the liver, which limited the production of reactive oxygen species (ROS) and promoted DNA damage resolution. We propose that this new reporter may be used to further advance our understanding of various physiological and pathophysiological p53 responses.
Collapse
Affiliation(s)
- Timothy J Humpton
- The Francis Crick Institute, London, NW1 1AT, United Kingdom
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
| | - Andreas K Hock
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
| | - Christos Kiourtis
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, United Kingdom
| | - Marco De Donatis
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, United Kingdom
| | - Frederic Fercoq
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
| | - Colin Nixon
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
| | - Sheila Bryson
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
| | - Douglas Strathdee
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
| | - Leo M. Carlin
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, United Kingdom
| | - Thomas G. Bird
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
- MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, EH164TJ, United Kingdom
| | - Karen Blyth
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, United Kingdom
| | - Karen H Vousden
- The Francis Crick Institute, London, NW1 1AT, United Kingdom
| |
Collapse
|
|
11
|
Rasheed M, Asghar R, Firdoos S, Ahmad N, Nazir A, Ullah KM, Li N, Zhuang F, Chen Z, Deng Y. A Systematic Review of Circulatory microRNAs in Major Depressive Disorder: Potential Biomarkers for Disease Prognosis. Int J Mol Sci 2022; 23:1294. [PMID: 35163214 PMCID: PMC8835958 DOI: 10.3390/ijms23031294] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/04/2023] Open
Abstract
Major depressive disorder (MDD) is a neuropsychiatric disorder, which remains challenging to diagnose and manage due to its complex endophenotype. In this aspect, circulatory microRNAs (cimiRNAs) offer great potential as biomarkers and may provide new insights for MDD diagnosis. Therefore, we systemically reviewed the literature to explore various cimiRNAs contributing to MDD diagnosis and underlying molecular pathways. A comprehensive literature survey was conducted, employing four databases from 2012 to January 2021. Out of 1004 records, 157 reports were accessed for eligibility criteria, and 32 reports meeting our inclusion criteria were considered for in-silico analysis. This study identified 99 dysregulated cimiRNAs in MDD patients, out of which 20 cimiRNAs found in multiple reports were selected for in-silico analysis. KEGG pathway analysis indicated activation of ALS, MAPK, p53, and P13K-Akt signaling pathways, while gene ontology analysis demonstrated that most protein targets were associated with transcription. In addition, chromosomal location analysis showed clustering of dysregulated cimiRNAs at proximity 3p22-p21, 9q22.32, and 17q11.2, proposing their coregulation with specific transcription factors primarily involved in MDD physiology. Further analysis of transcription factor sites revealed the existence of HIF-1, REST, and TAL1 in most cimiRNAs. These transcription factors are proposed to target genes linked with MDD, hypothesizing that first-wave cimiRNA dysregulation may trigger the second wave of transcription-wide changes, altering the protein expressions of MDD-affected cells. Overall, this systematic review presented a list of dysregulated cimiRNAs in MDD, notably miR-24-3p, let 7a-5p, miR-26a-5p, miR135a, miR-425-3p, miR-132, miR-124 and miR-16-5p as the most prominent cimiRNAs. However, various constraints did not permit us to make firm conclusions on the clinical significance of these cimiRNAs, suggesting the need for more research on single blood compartment to identify the biomarker potential of consistently dysregulated cimiRNAs in MDD, as well as the therapeutic implications of these in-silico insights.
Collapse
Affiliation(s)
- Madiha Rasheed
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Rabia Asghar
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Sundas Firdoos
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Nadeem Ahmad
- Department of Pharmacy, Abbottabad Campus, COMSATS University Islamabad, Abbottabad 22060, Pakistan;
| | - Amina Nazir
- Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan Industry North Road 202, Jinan 250100, China;
| | - Kakar Mohib Ullah
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Noumin Li
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Fengyuan Zhuang
- School of Biology and Medical Engineering, Beihang University, Beijing 100191, China;
| | - Zixuan Chen
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Yulin Deng
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| |
Collapse
|
|
12
|
Brackett CM, Greene KF, Aldrich AR, Trageser NH, Pal S, Molodtsov I, Kandar BM, Burdelya LG, Abrams SI, Gudkov AV. Signaling through TLR5 mitigates lethal radiation damage by neutrophil-dependent release of MMP-9. Cell Death Discov 2021; 7:266. [PMID: 34584068 PMCID: PMC8478872 DOI: 10.1038/s41420-021-00642-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/13/2021] [Accepted: 08/19/2021] [Indexed: 12/25/2022] Open
Abstract
Acute radiation syndrome (ARS) is a major cause of lethality following radiation disasters. A TLR5 agonist, entolimod, is among the most powerful experimental radiation countermeasures and shows efficacy in rodents and non-human primates as a prophylactic (radioprotection) and treatment (radiomitigation) modality. While the prophylactic activity of entolimod has been connected to the suppression of radiation-induced apoptosis, the mechanism by which entolimod functions as a radiomitigator remains poorly understood. Uncovering this mechanism has significant and broad-reaching implications for the clinical development and improvement of TLR5 agonists for use as an effective radiation countermeasure in scenarios of mass casualty resulting from accidental exposure to ionizing radiation. Here, we demonstrate that in contrast to radioprotection, neutrophils are essential for the radiomitigative activity of entolimod in a mouse model of lethal ARS. Neutrophils express functional TLR5 and rapidly exit the bone marrow (BM), accumulate in solid tissues, and release MMP-9 following TLR5 stimulation which is accompanied by an increase in the number of active hematopoietic pluripotent precursors (HPPs) in the BM. Importantly, recombinant MMP-9 by itself has radiomitigative activity and, in the absence of neutrophils, accelerates the recovery of the hematopoietic system. Unveiling this novel TLR5-neutrophil-MMP-9 axis of radiomitigation opens new opportunities for the development of efficacious radiation countermeasures to treat ARS following accidental radiation disasters.
Collapse
Affiliation(s)
- Craig M Brackett
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
| | - Kellee F Greene
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Alyssa R Aldrich
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Nicholas H Trageser
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Srabani Pal
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Ivan Molodtsov
- I.V. Davydovsky Clinical City Hospital, Moscow Department of Healthcare, Moscow, Russian Federation
| | - Bojidar M Kandar
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Lyudmila G Burdelya
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Scott I Abrams
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Andrei V Gudkov
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| |
Collapse
|
|
13
|
Checker R, Patwardhan RS, Jayakumar S, Maurya DK, Bandekar M, Sharma D, Sandur SK. Chemical and biological basis for development of novel radioprotective drugs for cancer therapy. Free Radic Res 2021; 55:595-625. [PMID: 34181503 DOI: 10.1080/10715762.2021.1876854] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ionizing radiation (IR) causes chemical changes in biological systems through direct interaction with the macromolecules or by causing radiolysis of water. This property of IR is harnessed in the clinic for radiotherapy in almost 50% of cancers patients. Despite the advent of stereotactic radiotherapy instruments and other advancements in shielding techniques, the inadvertent deposition of radiation dose in the surrounding normal tissue can cause late effects of radiation injury in normal tissues. Radioprotectors, which are chemical or biological agents, can reduce or mitigate these toxic side-effects of radiotherapy in cancer patients and also during radiation accidents. The desired characteristics of an ideal radioprotector include low chemical toxicity, high risk to benefit ratio and specific protection of normal cells against the harmful effects of radiation without compromising the cytotoxic effects of IR on cancer cells. Since reactive oxygen species (ROS) are the major contributors of IR mediated toxicity, plethora of studies have highlighted the potential role of antioxidants to protect against IR induced damage. However, owing to the lack of any clinically approved radioprotector against whole body radiation, researchers have shifted the focus toward finding alternate targets that could be exploited for the development of novel agents. The present review provides a comprehensive insight in to the different strategies, encompassing prime molecular targets, which have been employed to develop radiation protectors/countermeasures. It is anticipated that understanding such factors will lead to the development of novel strategies for increasing the outcome of radiotherapy by minimizing normal tissue toxicity.
Collapse
Affiliation(s)
- Rahul Checker
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Raghavendra S Patwardhan
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Sundarraj Jayakumar
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
| | - Dharmendra Kumar Maurya
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Mayuri Bandekar
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
| | - Deepak Sharma
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Santosh K Sandur
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| |
Collapse
|
|
14
|
Yuan ZH, Liu T, Wang H, Xue LX, Wang JJ. Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation. Front Cell Dev Biol 2021; 9:675617. [PMID: 34249928 PMCID: PMC8264768 DOI: 10.3389/fcell.2021.675617] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/04/2021] [Indexed: 12/14/2022] Open
Abstract
Exposure of tumor cells to ionizing radiation (IR) alters the microenvironment, particularly the fatty acid (FA) profile and activity. Moreover, abnormal FA metabolism, either catabolism or anabolism, is essential for synthesizing biological membranes and delivering molecular signals to induce ferroptotic cell death. The current review focuses on the bistable regulation characteristics of FA metabolism and explains how FA catabolism and anabolism pathway crosstalk harmonize different ionizing radiation-regulated ferroptosis responses, resulting in pivotal cell fate decisions. In summary, targeting key molecules involved in lipid metabolism and ferroptosis may amplify the tumor response to IR.
Collapse
Affiliation(s)
- Zhu-hui Yuan
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, China
| | - Tong Liu
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Hao Wang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, China
| | - Li-xiang Xue
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Biobank, Peking University Third Hospital, Beijing, China
| | - Jun-jie Wang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, China
| |
Collapse
|
|
15
|
p53 dynamics vary between tissues and are linked with radiation sensitivity. Nat Commun 2021; 12:898. [PMID: 33563973 PMCID: PMC7873198 DOI: 10.1038/s41467-021-21145-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 12/21/2020] [Indexed: 12/14/2022] Open
Abstract
Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies. p53 mediates the response to irradiation, however, tissues with similar levels of p53 have different radiation sensitivities. Here, the authors show that the in vivo p53 dynamics varies in these tissues after radiation, and the use of Mdm2 inhibitor to sustain p53 activity enhances radiosensitivity.
Collapse
|
|
16
|
Dong X, Kwan KM. Yin Yang 1 is critical for mid-hindbrain neuroepithelium development and involved in cerebellar agenesis. Mol Brain 2020; 13:104. [PMID: 32703236 PMCID: PMC7376712 DOI: 10.1186/s13041-020-00643-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 07/15/2020] [Indexed: 12/14/2022] Open
Abstract
The highly conserved and ubiquitously expressed transcription factor Yin Yang 1 (Yy1), was named after its dual functions of both activating and repressing gene transcription. Yy1 plays complex roles in various fundamental biological processes such as the cell cycle progression, cell proliferation, survival, and differentiation. Patients with dominant Yy1 mutations suffer from central nervous system (CNS) developmental defects. However, the role of Yy1 in mammalian CNS development remains to be fully elucidated. The isthmus organizer locates to the mid-hindbrain (MHB) boundary region and serves as the critical signaling center during midbrain and cerebellar early patterning. To study the function of Yy1 in mesencephalon/ rhombomere 1 (mes/r1) neuroepithelium development, we utilized the tissue-specific Cre-LoxP system and generated a conditional knockout mouse line to inactivate Yy1 in the MHB region. Mice with Yy1 deletion in the mes/r1 region displayed cerebellar agenesis and dorsal midbrain hypoplasia. The Yy1 deleted neuroepithelial cells underwent cell cycle arrest and apoptosis, with the concurrent changes of cell cycle regulatory genes expression, as well as activation of the p53 pathway. Moreover, we found that Yy1 is involved in the transcriptional activation of Wnt1 in neural stem cells. Thus, our work demonstrates the involvement of Yy1 in cerebellar agenesis and the critical function of Yy1 in mouse early MHB neuroepithelium maintenance and development.
Collapse
Affiliation(s)
- Xiaonan Dong
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Kin Ming Kwan
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China. .,Centre for Cell and Developmental Biology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China. .,State Key Laboratory of Agrobiotechnology (CUHK), The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.
| |
Collapse
|
|
17
|
Niklison-Chirou MV, Agostini M, Amelio I, Melino G. Regulation of Adult Neurogenesis in Mammalian Brain. Int J Mol Sci 2020; 21:ijms21144869. [PMID: 32660154 PMCID: PMC7402357 DOI: 10.3390/ijms21144869] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/02/2020] [Accepted: 07/07/2020] [Indexed: 12/15/2022] Open
Abstract
Adult neurogenesis is a multistage process by which neurons are generated and integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Neurogenesis plays a fundamental role in postnatal brain, where it is required for neuronal plasticity. Moreover, perturbation of adult neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative diseases. The interplay between extrinsic and intrinsic factors is fundamental in regulating neurogenesis. Over the past decades, several studies on intrinsic pathways, including transcription factors, have highlighted their fundamental role in regulating every stage of neurogenesis. However, it is likely that transcriptional regulation is part of a more sophisticated regulatory network, which includes epigenetic modifications, non-coding RNAs and metabolic pathways. Here, we review recent findings that advance our knowledge in epigenetic, transcriptional and metabolic regulation of adult neurogenesis in the SGZ of the hippocampus, with a special attention to the p53-family of transcription factors.
Collapse
Affiliation(s)
- Maria Victoria Niklison-Chirou
- Centre for Therapeutic Innovation (CTI-Bath), Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, UK;
- Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
| | - Massimiliano Agostini
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, 00133 Rome, Italy; (M.A.); (I.A.)
| | - Ivano Amelio
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, 00133 Rome, Italy; (M.A.); (I.A.)
- School of Life Sciences, University of Nottingham, Nottingham NG7 2HU, UK
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, 00133 Rome, Italy; (M.A.); (I.A.)
- Correspondence:
| |
Collapse
|
|
18
|
Zhu J, Singh M, Selivanova G, Peuget S. Pifithrin-α alters p53 post-translational modifications pattern and differentially inhibits p53 target genes. Sci Rep 2020; 10:1049. [PMID: 31974452 PMCID: PMC6978515 DOI: 10.1038/s41598-020-58051-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 01/06/2020] [Indexed: 11/19/2022] Open
Abstract
Pifithrin-α (PFT-α) is a small molecule which has been widely used as a specific inhibitor of p53 transcription activity. However, its molecular mechanism of action remains unclear. PFT-α has also been described to display potent p53-independent activity in cells. In this study, we addressed the mechanism of action of PFT-α. We found that PFT-α failed to prevent the effects of Mdm2 inhibitor Nutlin-3 on cell cycle and apoptosis in several cancer cell lines. However, PFT-α rescued normal primary fibroblasts from growth inhibition by Nutlin-3. PFT-α displayed a very limited effect on p53-dependent transcription upon its activation by Nutlin-3. Moreover, PFT-α inhibitory effect on transcription was highly dependent on the nature of the p53 target gene. PFT-α attenuated post-translational modifications of p53 without affecting total p53 protein level. Finally, we found that PFT-α can decrease the level of intracellular reactive oxygen species through activation of an aryl hydrocarbon receptor (AHR)-Nrf2 axis in a p53-independent manner. In conclusion, PFT-α inhibits only some aspects of p53 function, therefore it should be used with extreme caution to study p53-dependent processes.
Collapse
Affiliation(s)
- Jiawei Zhu
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Madhurendra Singh
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Galina Selivanova
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
| | - Sylvain Peuget
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
| |
Collapse
|
|
19
|
Wang JYJ. Cell Death Response to DNA Damage. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2019; 92:771-779. [PMID: 31866794 PMCID: PMC6913835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
The cell death response to DNA damage is discussed in this Perspectives piece with cancer as the backdrop because DNA damaging agents (DDA) are widely used to treat cancer. From decades of clinical results, we learn that DDA have cured some cancers but their toxicity is temporary in most cancers due to emergence of DDA-resistant cancer cells. Investigation of DDA-activated genes, proteins, and pathways, known collectively as the DNA damage response (DDR), has uncovered the inner workings of DDR that protect the genome to sustain life. Paradoxically, however, DDR can also activate death. Current knowledge on DDA-activated death and hypotheses for how DDR may determine when and where to execute death are discussed. Given that cancer cells suffer from DDR defects, which account for their initial sensitivity to DDA, future therapeutic development may exploit those cancer-specific DDR defects to selectively create death-inducing DNA lesions, without using DDA, to kill DDA-resistant cancers.
Collapse
Affiliation(s)
- Jean Y. J. Wang
- To whom all correspondence should be addressed: Jean Y. J. Wang, PhD, Department of Cellular & Molecular Medicine, University of California, San Diego, School of Medicine, CMME 2059, 9500 Gilman Drive, La Jolla, CA, 92093-0660; Tel: (858) 534-6253,
| |
Collapse
|
|
20
|
Sun F, Wang J, Wu X, Yang CS, Zhang J. Selenium nanoparticles act as an intestinal p53 inhibitor mitigating chemotherapy-induced diarrhea in mice. Pharmacol Res 2019; 149:104475. [PMID: 31593755 DOI: 10.1016/j.phrs.2019.104475] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 09/21/2019] [Accepted: 10/01/2019] [Indexed: 12/27/2022]
Abstract
Selenium, at high-dose levels approaching its toxicity, protects tissues from dose-limiting toxicities of many cancer chemotherapeutics without compromising their therapeutic effects on tumors, there by allowing the delivery of higher chemotherapeutic doses to achieve increased cure rate. In this regard, selenium nanoparticles (SeNPs), which show the lowest toxicity among extensively investigated selenium compounds including methylselenocysteine and selenomethionine, are more promising for application. The key issue remains to be resolved is whether low-toxicity SeNPs possess a selective protective mechanism. p53 or p53-regulated thrombospondin-1 has each been confirmed to be an appropriate target for therapeutic suppression to reduce side effects of anticancer therapy. The present study demonstrated that SeNPs transiently suppressed the expression of many intestinal p53-associated genes in healthy mice. SeNPs did not interfere with tumor-suppressive effect of nedaplatin, a cisplatin analogue; however, effectively reduced nedaplatin-evoked diarrhea. Nedaplatin-induced diarrhea was associated with activation of intestinal p53 and high expression of intestinal thrombospondin-1. The preventive effect of SeNPs on nedaplatin-induced diarrhea was correlated with a powerful concomitant suppression of p53 and thrombospondin-1. Moreover, the high-dose SeNPs used in the present study did not suppress growth nor caused liver and kidney injuries as well as alterations of hematological parameters in healthy mice. Overall, the present study reveals that chemotherapeutic selectivity conferred by SeNPs involves a dual suppression of two well-documented targets, the p53 and thrombospondin-1, providing mechanistic and pharmacologic insights on low-toxicity SeNPs as a potential chemoprotectant for mitigating chemotherapy-induced diarrhea.
Collapse
Affiliation(s)
- Feng Sun
- Laboratory of Redox Biology, School of Tea & Food Science, State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, Anhui, China
| | - Jiajia Wang
- Laboratory of Redox Biology, School of Tea & Food Science, State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, Anhui, China
| | - Ximing Wu
- Laboratory of Redox Biology, School of Tea & Food Science, State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, Anhui, China
| | - Chung S Yang
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Jinsong Zhang
- Laboratory of Redox Biology, School of Tea & Food Science, State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, Anhui, China.
| |
Collapse
|
|
21
|
Xue Y, San Luis B, Lane DP. Intratumour heterogeneity of p53 expression; causes and consequences. J Pathol 2019; 249:274-285. [PMID: 31322742 DOI: 10.1002/path.5328] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 06/27/2019] [Accepted: 07/11/2019] [Indexed: 12/23/2022]
Abstract
Genomic alterations in different types of cancer have been identified by comprehensive sequencing methodologies, revealing TP53 as the most frequently mutated gene across the majority of human cancer types. Cytotoxic treatments are still major cancer therapy strategies but cancer recurrence due to therapy resistance is a major challenge. Resistant cell populations may be associated with TP53 mutant clones exhibiting abnormal p53 expression patterns in tumours. Given data that levels of mutant p53 influence cancer cell growth and survival, understanding the mechanisms underlying intratumour heterogeneity of p53 can be exploited to design strategies that improve patient survival. The patterns of p53 protein examined by immunohistochemistry of both premalignant and malignant tissues are complex, ranging from intense staining of all tumour cell nuclei to complete absence of staining and with many intermediate phenotypes. Animal models that express only mutant proteins and adoption of international standards for terminology have brought greater clarity to understanding the causes of variation and are at the same time demonstrating the utility of p53 in oncology. In addition to p53 mutation, MDM2 and chaperone activities, gene copy number and TP53 mRNA levels linked to proliferative activity and differentiation are all now established as causes of variation in p53 staining, with clinical implications. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Yuezhen Xue
- p53 Laboratory, A*STAR, Singapore, Singapore
| | | | | |
Collapse
|
|
22
|
Rodriguez-Ramirez C, Nör JE. p53 and Cell Fate: Sensitizing Head and Neck Cancer Stem Cells to Chemotherapy. Crit Rev Oncog 2019; 23:173-187. [PMID: 30311573 DOI: 10.1615/critrevoncog.2018027353] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Head and neck cancers are deadly diseases that are diagnosed annually in approximately half a million individuals worldwide. Growing evidence supporting a role for cancer stem cells (CSCs) in the pathobiology of head and neck cancers has led to increasing interest in identifying therapeutics to target these cells. Apart from the canonical tumor-suppressor functions of p53, emerging research supports a significant role for this protein in physiological stem cell and CSC maintenance and reprogramming. Therefore, p53 has become a promising target to sensitize head and neck CSCs to chemotherapy. In this review, we highlight the role of p53 in stem cell maintenance and discuss potential implications of targeting p53 to treat patients with head and neck cancers.
Collapse
Affiliation(s)
- Christie Rodriguez-Ramirez
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109
| | - Jacques E Nör
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI; Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
| |
Collapse
|
|
23
|
Hu Y, Dai J, Zong G, Xiao J, Guo X, Dai Y, Lu Z, Wan R. Restoration of p53 acetylation by HDAC inhibition permits the necrosis/apoptosis switch of pancreatic ainar cell during experimental pancreatitis in mice. J Cell Physiol 2019; 234:21988-21998. [PMID: 31058328 DOI: 10.1002/jcp.28761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 04/07/2019] [Accepted: 04/10/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Yangyang Hu
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Juanjuan Dai
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Guanzhao Zong
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Jingbo Xiao
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Xingya Guo
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Yiqi Dai
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Zhanjun Lu
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Rong Wan
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| |
Collapse
|
|
24
|
TP53 Polymorphism Contributes to the Susceptibility to Bipolar Disorder but Not to Schizophrenia in the Chinese Han Population. J Mol Neurosci 2019; 68:679-687. [DOI: 10.1007/s12031-019-01330-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 04/25/2019] [Indexed: 12/15/2022]
|
|
25
|
Differentiation of Human Embryonic Stem Cells to Sympathetic Neurons: A Potential Model for Understanding Neuroblastoma Pathogenesis. Stem Cells Int 2018; 2018:4391641. [PMID: 30515222 PMCID: PMC6236576 DOI: 10.1155/2018/4391641] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 08/17/2018] [Accepted: 09/16/2018] [Indexed: 12/31/2022] Open
Abstract
Background and Aims Previous studies modelling human neural crest differentiation from stem cells have resulted in a low yield of sympathetic neurons. Our aim was to optimise a method for the differentiation of human embryonic stem cells (hESCs) to sympathetic neuron-like cells (SN) to model normal human SNS development. Results Using stromal-derived inducing activity (SDIA) of PA6 cells plus BMP4 and B27 supplements, the H9 hESC line was differentiated to neural crest stem-like cells and SN-like cells. After 7 days of PA6 cell coculture, mRNA expression of SNAIL and SOX-9 neural crest specifier genes and the neural marker peripherin (PRPH) increased. Expression of the pluripotency marker OCT 4 decreased, whereas TP53 and LIN28B expression remained high at levels similar to SHSY5Y and IMR32 neuroblastoma cell lines. A 5-fold increase in the expression of the catecholaminergic marker tyrosine hydroxylase (TH) and the noradrenergic marker dopamine betahydroxylase (DBH) was observed by day 7 of differentiation. Fluorescence-activated cell sorting for the neural crest marker p75, enriched for cells expressing p75, DBH, TH, and PRPH, was more specific than p75 neural crest stem cell (NCSC) microbeads. On day 28 post p75 sorting, dual immunofluorescence identified sympathetic neurons by PRPH and TH copositivity cells in 20% of the cell population. Noradrenergic sympathetic neurons, identified by copositivity for both PHOX2B and DBH, were present in 9.4% ± 5.5% of cells. Conclusions We have optimised a method for noradrenergic SNS development using the H9 hESC line to improve our understanding of normal human SNS development and, in a future work, the pathogenesis of neuroblastoma.
Collapse
|
|
26
|
Enane FO, Saunthararajah Y, Korc M. Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells. Cell Death Dis 2018; 9:912. [PMID: 30190481 PMCID: PMC6127320 DOI: 10.1038/s41419-018-0919-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 07/23/2018] [Accepted: 07/24/2018] [Indexed: 12/24/2022]
Abstract
Chemotherapeutic drugs have a common intent to activate apoptosis in tumor cells. However, master regulators of apoptosis (e.g., p53, p16/CDKN2A) are frequently genetically inactivated in cancers, resulting in multidrug resistance. An alternative, p53-independent method for terminating malignant proliferation is to engage terminal-differentiation. Normally, the exponential proliferation of lineage-committed progenitors, coordinated by the master transcription factor (TF) MYC, is self-limited by forward-differentiation to terminal lineage-fates. In cancers, however, this exponential proliferation is disengaged from terminal-differentiation. The mechanisms underlying this decoupling are mostly unknown. We performed a systematic review of published literature (January 2007-June 2018) to identify gene pathways linked to differentiation-failure in three treatment-recalcitrant cancers: hepatocellular carcinoma (HCC), ovarian cancer (OVC), and pancreatic ductal adenocarcinoma (PDAC). We analyzed key gene alterations in various apoptosis, proliferation and differentiation pathways to determine whether it is possible to predict treatment outcomes and suggest novel therapies. Poorly differentiated tumors were linked to poorer survival across histologies. Our analyses suggested loss-of-function events to master TF drivers of lineage-fates and their cofactors as being linked to differentiation-failure: genomic data in TCGA and ICGC databases demonstrated frequent haploinsufficiency of lineage master TFs (e.g., GATA4/6) in poorly differentiated tumors; the coactivators that these TFs use to activate genes (e.g. ARID1A, PBRM1) were also frequently inactivated by genetic mutation and/or deletion. By contrast, corepressor components (e.g., DNMT1, EED, UHRF1, and BAZ1A/B), that oppose coactivators to repress or turn off genes, were frequently amplified instead, and the level of amplification was highest in poorly differentiated lesions. This selection by neoplastic evolution towards unbalanced activity of transcriptional corepressors suggests these enzymes as candidate targets for inhibition aiming to re-engage forward-differentiation. This notion is supported by both pre-clinical and clinical trial literature.
Collapse
Affiliation(s)
- Francis O Enane
- Department of Medicine, Indiana University School of Medicine Indianapolis, Indianapolis, IN, 46202, USA.
| | - Yogen Saunthararajah
- Department of Hematology and Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, 44195, USA
- Department of Translational Hematology and Oncology Research, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Murray Korc
- Department of Medicine, Indiana University School of Medicine Indianapolis, Indianapolis, IN, 46202, USA.
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- The Pancreatic Cancer Signature Center at Indiana University Purdue University Indianapolis and Indiana University Simon Cancer, Indianapolis, IN, 46202, USA.
| |
Collapse
|
|
27
|
Gao X, Mi Y, Guo N, Xu H, Jiang P, Zhang R, Xu L, Gou X. Glioma in Schizophrenia: Is the Risk Higher or Lower? Front Cell Neurosci 2018; 12:289. [PMID: 30233327 PMCID: PMC6129591 DOI: 10.3389/fncel.2018.00289] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 08/13/2018] [Indexed: 12/17/2022] Open
Abstract
Whether persons with schizophrenia have a higher or lower incidence of cancer has been discussed for a long time. Due to the complex mechanisms and characteristics of different types of cancer, it is difficult to evaluate the exact relationship between cancers and schizophrenia without considering the type of tumor. Schizophrenia, a disabling mental illness that is now recognized as a neurodevelopmental disorder, is more correlated with brain tumors, such as glioma, than other types of tumors. Thus, we mainly focused on the relationship between schizophrenia and glioma morbidity. Glioma tumorigenesis and schizophrenia may share similar mechanisms; gene/pathway disruption would affect neurodevelopment and reduce the risk of glioma. The molecular defects of disrupted-in-schizophrenia-1 (DISC1), P53, brain-derived neurotrophic factor (BDNF) and C-X-C chemokine receptors type 4 (CXCR4) involved in schizophrenia pathogenesis might play opposite roles in glioma development. Many microRNAs (miRNAs) such as miR-183, miR-9, miR-137 and miR-126 expression change may be involved in the cross talk between glioma prevalence and schizophrenia. Finally, antipsychotic drugs may have antitumor effects. All these factors show that persons with schizophrenia have a decreased incidence of glioma; therefore, epidemiological investigation and studies comparing genetic and epigenetic aberrations involved in both of these complex diseases should be performed. These studies can provide more insightful knowledge about glioma and schizophrenia pathophysiology and help to determine the target/strategies for the prevention and treatment of the two diseases.
Collapse
Affiliation(s)
- Xingchun Gao
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic Medical Sciences & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China.,State Key Laboratory of Military Stomatology, Department of Anesthesiology, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Yajing Mi
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic Medical Sciences & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Na Guo
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic Medical Sciences & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Hao Xu
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic Medical Sciences & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China.,State Key Laboratory of Military Stomatology, Department of Anesthesiology, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Pengtao Jiang
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic Medical Sciences & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Ruisan Zhang
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic Medical Sciences & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Lixian Xu
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic Medical Sciences & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China.,State Key Laboratory of Military Stomatology, Department of Anesthesiology, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Xingchun Gou
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic Medical Sciences & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| |
Collapse
|
|
28
|
El Husseini N, Hales BF. Hydroxyurea embryotoxicity is enhanced in P53-deficient mice. Reprod Toxicol 2018; 81:28-33. [PMID: 29940331 DOI: 10.1016/j.reprotox.2018.06.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/14/2018] [Accepted: 06/19/2018] [Indexed: 12/01/2022]
Abstract
Hydroxyurea, a ribonucleotide reductase inhibitor, is a potent teratogen in mice, causing severe limb and skeletal defects. The exposure of gestation day nine murine embryos to hydroxyurea elicits an early embryonic stress response that involves activation of the P53 transcription factor. The impact of this P53 activation on the embryotoxicity of hydroxyurea- is not known. The goal of this study was to test the hypothesis that P53 acts to suppress hydroxyurea embryotoxicity. Trp53+/- timed pregnant mice were treated with saline or hydroxyurea (200 or 400 mg/kg) on gestation day nine; fetuses were examined for viability and external and skeletal malformations on gestation day eighteen. Neither the deletion of Trp53 nor hydroxyurea treatment significantly affected fetal growth although a trend towards a decrease in fetal weights was observed in Trp53-/- fetuses. However, hydroxyurea induced a significantly higher incidence of malformations and resorptions in Trp53-/- fetuses compared to their wildtype littermates. Thus, fetal P53 genotype is an important determinant of the effects of hydroxyurea on organogenesis-stage embryos.
Collapse
Affiliation(s)
- Nazem El Husseini
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Barbara F Hales
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
| |
Collapse
|
|
29
|
Oufi HG. The cytogenetic effects of silibinin alone and in combination with methotrexate in mouse bone marrow. Eur J Pharmacol 2018; 824:179-184. [DOI: 10.1016/j.ejphar.2018.02.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 02/08/2018] [Accepted: 02/09/2018] [Indexed: 02/02/2023]
|
|
30
|
Quercetin enhances chemotherapeutic effect of doxorubicin against human breast cancer cells while reducing toxic side effects of it. Biomed Pharmacother 2018; 100:441-447. [DOI: 10.1016/j.biopha.2018.02.055] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 02/12/2018] [Accepted: 02/13/2018] [Indexed: 11/22/2022] Open
|
|
31
|
Zwezdaryk K, Sullivan D, Saifudeen Z. The p53/Adipose-Tissue/Cancer Nexus. Front Endocrinol (Lausanne) 2018; 9:457. [PMID: 30158901 PMCID: PMC6104444 DOI: 10.3389/fendo.2018.00457] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 07/24/2018] [Indexed: 12/16/2022] Open
Abstract
Obesity and the resultant metabolic complications have been associated with an increased risk of cancer. In addition to the systemic metabolic disturbances in obesity that are associated with cancer initiation and progression, the presence of adipose tissue in the tumor microenvironment (TME) contributes significantly to malignancy through direct cell-cell interaction or paracrine signaling. This chronic inflammatory state can be maintained by p53-associated mechanisms. Increased p53 levels that are observed in obesity exacerbate the release of inflammatory cytokines that fuel cancer initiation and progression. Dysregulated adipose tissue signaling from the TME can reprogram tumor cell metabolism. The links between p53, cellular metabolism and adipose tissue dysfunction and how they relate to cancer, will be presented in this review.
Collapse
Affiliation(s)
- Kevin Zwezdaryk
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
- *Correspondence: Kevin Zwezdaryk
| | - Deborah Sullivan
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
- Deborah Sullivan
| | - Zubaida Saifudeen
- Department of Pediatrics, Section of Nephrology, Tulane University School of Medicine, New Orleans, LA, United States
- Zubaida Saifudeen
| |
Collapse
|
|
32
|
Noda N, Awais R, Sutton R, Awais M, Ozawa T. Dynamic monitoring of p53 translocation to mitochondria for the analysis of specific inhibitors using luciferase-fragment complementation. Biotechnol Bioeng 2017; 114:2818-2827. [DOI: 10.1002/bit.26407] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 08/14/2017] [Accepted: 08/17/2017] [Indexed: 11/10/2022]
Affiliation(s)
- Natsumi Noda
- Department of Chemistry, School of Science; The University of Tokyo; Bunkyo-ku Tokyo Japan
| | - Raheela Awais
- School of Life Sciences; University of Liverpool; Liverpool United Kingdom
| | - Robert Sutton
- NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, University of Liverpool; Royal Liverpool University Hospital; Liverpool United Kingdom
| | - Muhammad Awais
- NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, University of Liverpool; Royal Liverpool University Hospital; Liverpool United Kingdom
| | - Takeaki Ozawa
- Department of Chemistry, School of Science; The University of Tokyo; Bunkyo-ku Tokyo Japan
| |
Collapse
|
|
33
|
Abstract
p53 is best identified as a tumor suppressor for its transcriptional control of genes involved in cell cycle progression and apoptosis. Beyond its irrefutable involvement in restraining unchecked cell proliferation, research over the past several years has indicated a requirement for p53 function in sustaining normal development. Here I summarize the role of p53 in embryonic development, with a focus on knowledge gained from p53 loss and overexpression during kidney development. In contrast to its classical role in suppressing proliferative pathways, p53 positively regulates nephron progenitor cell (NPC) renewal. Emerging evidence suggests p53 may control cell fate decisions by preserving energy metabolism homeostasis of progenitors in the nephrogenic niche. Maintaining a critical level of p53 function appears to be a prerequisite for optimal nephron endowment. Defining the molecular networks targeted by p53 in the NPC may well provide new targets not only for regenerative medicine but also for cancer treatment.
Collapse
Affiliation(s)
- Zubaida Saifudeen
- Department of Pediatrics, Section of Pediatric Nephrology, Tulane University School of Medicine, 1430 Tulane Avenue, SL37, New Orleans, LA, 70112, USA.
| |
Collapse
|
|
34
|
Zheng S, Koh XY, Goh HC, Rahmat SAB, Hwang LA, Lane DP. Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity. Cancer Res 2017; 77:4342-4354. [DOI: 10.1158/0008-5472.can-17-0424] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 05/08/2017] [Accepted: 06/19/2017] [Indexed: 11/16/2022]
|
|
35
|
Mahmood S, Evinová A, Škereňová M, Ondrejka I, Lehotský J. Association of EGF, IGFBP-3 and TP53 Gene Polymorphisms with Major Depressive Disorder in Slovak Population. Cent Eur J Public Health 2017; 24:223-230. [PMID: 27755861 DOI: 10.21101/cejph.a4301] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 04/27/2016] [Indexed: 11/15/2022]
Abstract
BACKGROUND Major depressive disorder (MDD) is a main public health concern worldwide. Despite extensive investigations, the exact mechanisms responsible for MDD have not been identified. Epidermal growth factor (EGF) and insulin growth factor binding protein-3 (IGFBP-3) are involved in brain function. Tumour suppressor protein p53 is widely involved in neuronal death in response to different forms of acute insults and neurological disorders. The present study focuses on the possible associations of the single-nucleotide polymorphisms (SNP) of EGF A61G (rs4444903), IGFBP-3 C32G (rs2854746) and TP53 G72C (rs1042522) genes with MDD risk in the Slovak population. METHODS The present case-control association study was carried out in 111 confirmed MDD patients and 207 healthy subjects. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS Logistic regression analysis showed no association between SNPs of selected genes and MDD risk in the Slovak population. However, the stratification of individuals by gender revealed that males carrying IGFBP-3 G alleles (G32G or GG) had marginally increased risk for developing MDD as compared to CC homozygous males (p=0.09). In women, inverse association was observed between SNP rs1042522 and MDD risk (p=0.04 for recessive model). CONCLUSION Our results suggest the protective effect of minor allele 72C of TP53 gene towards MDD. The disruption of mechanisms involved in cell survival and death regulation may be involved in pathophysiology of MDD.
Collapse
Affiliation(s)
- Silvia Mahmood
- Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Biomedical Centre Martin (BioMed Martin), Martin, Slovakia.,Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Andrea Evinová
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Mária Škereňová
- Department of Clinical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, Martin, Slovakia
| | - Igor Ondrejka
- Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Clinic of Psychiatry, Martin University Hospital, Martin, Slovakia
| | - Ján Lehotský
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.,Department of Neurosciences, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Biomedical Centre Martin (BioMed Martin), Martin, Slovakia
| |
Collapse
|
|
36
|
Tanikawa C, Zhang YZ, Yamamoto R, Tsuda Y, Tanaka M, Funauchi Y, Mori J, Imoto S, Yamaguchi R, Nakamura Y, Miyano S, Nakagawa H, Matsuda K. The Transcriptional Landscape of p53 Signalling Pathway. EBioMedicine 2017; 20:109-119. [PMID: 28558959 PMCID: PMC5478243 DOI: 10.1016/j.ebiom.2017.05.017] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 05/09/2017] [Accepted: 05/10/2017] [Indexed: 02/07/2023] Open
Abstract
Although recent cancer genomics studies have identified a large number of genes that were mutated in human cancers, p53 remains as the most frequently mutated gene. To further elucidate the p53-signalling network, we performed transcriptome analysis on 24 tissues in p53+/+ or p53−/− mice after whole-body X-ray irradiation. Here we found transactivation of a total of 3551 genes in one or more of the 24 tissues only in p53+/+ mice, while 2576 genes were downregulated. p53 mRNA expression level in each tissue was significantly associated with the number of genes upregulated by irradiation. Annotation using TCGA (The Cancer Genome Atlas) database revealed that p53 negatively regulated mRNA expression of several cancer therapeutic targets or pathways such as BTK, SYK, and CTLA4 in breast cancer tissues. In addition, stomach exhibited the induction of Krt6, Krt16, and Krt17 as well as loricrin, an epidermal differentiation marker, after the X-ray irradiation only in p53+/+ mice, implying a mechanism to protect damaged tissues by rapid induction of differentiation. Our comprehensive transcriptome analysis elucidated tissue specific roles of p53 and its signalling networks in DNA-damage response that will enhance our understanding of cancer biology.
Transcriptome analysis across 24 mouse tissues identified a total of 3551 p53-induced genes and 2576 p53-repressed genes. p53 mRNA in each tissue was associated with the numbers of p53-induced/repressed genes. p53 would protect gastric epithelial cells from X-ray irradiation through the induction of differentiation and keratinization p53 is the most frequently mutated tumor-suppressor that functions as a transcription factor. Transcriptome analysis of 280 samples from 24 tissues identified 3551 p53-induced and 2576 p53-repressed genes. p53 negatively regulated several cancer therapeutic targets, BTK, SYK, and CTLA4 in breast cancer tissues. Majority of X-ray responsive genes were regulated by p53 and p53 mRNA expression in each tissue was associated with the numbers of p53-induced and repressed genes, demonstrating its crucial roles in damage response. The whole-body transcriptome analysis revealed that p53 would protect gastric epithelial cells from X-ray irradiation through the induction of differentiation and keratinization.
Collapse
Affiliation(s)
- Chizu Tanikawa
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Yao-Zhong Zhang
- Laboratory of DNA information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Ryuta Yamamoto
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Yusuke Tsuda
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Masami Tanaka
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Yuki Funauchi
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Jinichi Mori
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Laboratory of Clinical Genome Sequence, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| | - Seiya Imoto
- Laboratory of DNA information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Rui Yamaguchi
- Laboratory of DNA information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Yusuke Nakamura
- Department of Medicine, Center for Personalized Therapeutics, The University of Chicago, USA; Department of Surgery, Center for Personalized Therapeutics, The University of Chicago, USA
| | - Satoru Miyano
- Laboratory of DNA information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hidewaki Nakagawa
- Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
| | - Koichi Matsuda
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Laboratory of Clinical Genome Sequence, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
| |
Collapse
|
|
37
|
|
|
38
|
The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells. Aging (Albany NY) 2016; 7:854-68. [PMID: 26540407 PMCID: PMC4637210 DOI: 10.18632/aging.100831] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Medulloblastoma (MB), a primitive neuroectodermal tumor, is the most common malignant childhood brain tumor and remains incurable in about a third of patients. Currently, survivors carry a significant burden of late treatment effects. The p53 tumor suppressor protein plays a crucial role in influencing cell survival in response to cellular stress and while the p53 pathway is considered a key determinant of anti-tumor responses in many tumors, its role in cell survival in MB is much less well defined. Herein, we report that the experimental drug VMY-1-103 acts through induction of a partial DNA damage-like response as well induction of non-survival autophagy. Surprisingly, the genetic or chemical silencing of p53 significantly enhanced the cytotoxic effects of both VMY and the DNA damaging drug, doxorubicin. The inhibition of p53 in the presence of VMY revealed increased late stage apoptosis, increased DNA fragmentation and increased expression of genes involved in apoptosis, including CAPN12 and TRPM8, p63, p73, BIK, EndoG, CIDEB, P27Kip1 and P21cip1. These data provide the groundwork for additional studies on VMY as a therapeutic drug and support further investigations into the intriguing possibility that targeting p53 function may be an effective means of enhancing clinical outcomes in MB.
Collapse
|
|
39
|
Danilova N, Gazda HT. Ribosomopathies: how a common root can cause a tree of pathologies. Dis Model Mech 2016; 8:1013-26. [PMID: 26398160 PMCID: PMC4582105 DOI: 10.1242/dmm.020529] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Defects in ribosome biogenesis are associated with a group of diseases called the ribosomopathies, of which Diamond-Blackfan anemia (DBA) is the most studied. Ribosomes are composed of ribosomal proteins (RPs) and ribosomal RNA (rRNA). RPs and multiple other factors are necessary for the processing of pre-rRNA, the assembly of ribosomal subunits, their export to the cytoplasm and for the final assembly of subunits into a ribosome. Haploinsufficiency of certain RPs causes DBA, whereas mutations in other factors cause various other ribosomopathies. Despite the general nature of their underlying defects, the clinical manifestations of ribosomopathies differ. In DBA, for example, red blood cell pathology is especially evident. In addition, individuals with DBA often have malformations of limbs, the face and various organs, and also have an increased risk of cancer. Common features shared among human DBA and animal models have emerged, such as small body size, eye defects, duplication or overgrowth of ectoderm-derived structures, and hematopoietic defects. Phenotypes of ribosomopathies are mediated both by p53-dependent and -independent pathways. The current challenge is to identify differences in response to ribosomal stress that lead to specific tissue defects in various ribosomopathies. Here, we review recent findings in this field, with a particular focus on animal models, and discuss how, in some cases, the different phenotypes of ribosomopathies might arise from differences in the spatiotemporal expression of the affected genes. Summary: This paper reviews recent data on Diamond Blackfan anemia and discusses them in connection with other ribosomopathies.
Collapse
Affiliation(s)
- Nadia Danilova
- Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA 90095, USA
| | - Hanna T Gazda
- Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA Broad Institute, Cambridge, MA 02142, USA
| |
Collapse
|
|
40
|
Emerging targets for radioprotection and radiosensitization in radiotherapy. Tumour Biol 2016; 37:11589-11609. [DOI: 10.1007/s13277-016-5117-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 06/09/2016] [Indexed: 01/12/2023] Open
|
|
41
|
Thayer KM, Beyer GA. Energetic Landscape of MDM2-p53 Interactions by Computational Mutagenesis of the MDM2-p53 Interaction. PLoS One 2016; 11:e0147806. [PMID: 26992014 PMCID: PMC4798270 DOI: 10.1371/journal.pone.0147806] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 12/01/2015] [Indexed: 11/18/2022] Open
Abstract
The ubiquitin ligase MDM2, a principle regulator of the tumor suppressor p53, plays an integral role in regulating cellular levels of p53 and thus a prominent role in current cancer research. Computational analysis used MUMBO to rotamerize the MDM2-p53 crystal structure 1YCR to obtain an exhaustive search of point mutations, resulting in the calculation of the ΔΔG comprehensive energy landscape for the p53-bound regulator. The results herein have revealed a set of residues R65-E69 on MDM2 proximal to the p53 hydrophobic binding pocket that exhibited an energetic profile deviating significantly from similar residues elsewhere in the protein. In light of the continued search for novel competitive inhibitors for MDM2, we discuss possible implications of our findings on the drug discovery field.
Collapse
Affiliation(s)
- Kelly M. Thayer
- Department of Chemistry, 124 Raymond Avenue, Poughkeepsie, New York 12604, United States of America
- Wesleyan University, Hall Atwater Laboratories, Middletown, Connecticut 06459, United States of America
- * E-mail:
| | - George A. Beyer
- Biochemistry Program, Vassar College, 124 Raymond Avenue, Poughkeepsie, New York 12604, United States of America
| |
Collapse
|
|
42
|
Chen J. The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. Cold Spring Harb Perspect Med 2016; 6:a026104. [PMID: 26931810 DOI: 10.1101/cshperspect.a026104] [Citation(s) in RCA: 773] [Impact Index Per Article: 85.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
P53 is a transcription factor highly inducible by many stress signals such as DNA damage, oncogene activation, and nutrient deprivation. Cell-cycle arrest and apoptosis are the most prominent outcomes of p53 activation. Many studies showed that p53 cell-cycle and apoptosis functions are important for preventing tumor development. p53 also regulates many cellular processes including metabolism, antioxidant response, and DNA repair. Emerging evidence suggests that these noncanonical p53 activities may also have potent antitumor effects within certain context. This review focuses on the cell-cycle arrest and apoptosis functions of p53, their roles in tumor suppression, and the regulation of cell fate decision after p53 activation.
Collapse
Affiliation(s)
- Jiandong Chen
- Molecular Oncology Department, Moffitt Cancer Center, Tampa, Florida 33612
| |
Collapse
|
|
43
|
Kamran MZ, Ranjan A, Kaur N, Sur S, Tandon V. Radioprotective Agents: Strategies and Translational Advances. Med Res Rev 2016; 36:461-93. [PMID: 26807693 DOI: 10.1002/med.21386] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 12/15/2015] [Accepted: 01/01/2016] [Indexed: 01/08/2023]
Abstract
Radioprotectors are agents required to protect biological system exposed to radiation, either naturally or through radiation leakage, and they protect normal cells from radiation injury in cancer patients undergoing radiotherapy. It is imperative to study radioprotectors and their mechanism of action comprehensively, looking at their potential therapeutic applications. This review intimately chronicles the rich intellectual, pharmacological story of natural and synthetic radioprotectors. A continuous effort is going on by researchers to develop clinically promising radioprotective agents. In this article, for the first time we have discussed the impact of radioprotectors on different signaling pathways in cells, which will create a basis for scientific community working in this area to develop novel molecules with better therapeutic efficacy. The bright future of exceptionally noncytotoxic derivatives of bisbenzimidazoles is also described as radiomodulators. Amifostine, an effective radioprotectant, has been approved by the FDA for limited clinical use. However, due to its adverse side effects, it is not routinely used clinically. Recently, CBLB502 and several analog of a peptide are under clinical trial and showed high success against radiotherapy in cancer. This article reviews the different types of radioprotective agents with emphasis on the strategies for the development of novel radioprotectors for drug development. In addition, direction for future strategies relevant to the development of radioprotectors is also addressed.
Collapse
Affiliation(s)
- Mohammad Zahid Kamran
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Atul Ranjan
- Kansas University of Medical Center, Kansas City, KS, 66160
| | - Navrinder Kaur
- Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Souvik Sur
- Department of Chemistry, University of Delhi, Delhi, 110007, India
| | - Vibha Tandon
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.,Department of Chemistry, University of Delhi, Delhi, 110007, India
| |
Collapse
|
|
44
|
Eng HY, Wang CI, Xue Y, Lee CY, Zulkifli SB, Chiam PC, Ghadessy FJ, Lane DP. Enhanced antigen detection in immunohistochemical staining using a 'digitized' chimeric antibody. Protein Eng Des Sel 2015; 29:11-21. [PMID: 26508747 DOI: 10.1093/protein/gzv054] [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: 07/11/2015] [Accepted: 09/25/2015] [Indexed: 11/12/2022] Open
Abstract
The immunohistochemical (IHC) staining of mouse tissue sections using antibodies of mouse origin can result in high nonspecific background due to the staining of endogenous immunoglobulins (Igs) by enzyme-conjugated secondary antibodies. In order to obviate this issue, we developed a chimeric mouse-human anti-p53 monoclonal antibody (MH242) by grafting the variable regions of a known mouse antibody into a human Ig scaffold. This facilitated use of an anti-human secondary antibody, and resulted in near-zero background when compared with its parental mouse monoclonal antibody (PAb242). Furthermore, the chimeric antibody enabled reproducible detection of mutant p53 (homozygous R172H) expression in mouse tissue, an observation hitherto largely equivocal based on the use of existing antibodies. The approach we describe leads to the generation of tractable antibody reagents, whose integrity can be readily verified through DNA sequencing of expressor plasmids. The wide-spread adoption of such 'digitized' antibodies should reduce experimental disparities that can commonly arise through variations in antibody quality.
Collapse
Affiliation(s)
- Hui-Yan Eng
- p53 Laboratory, 8A Biomedical Grove, Immunos #06-06, Singapore 138648, Singapore
| | - Cheng-I Wang
- Singapore Immunology Network, 8A Biomedical Grove, Singapore 138648, Singapore
| | - Yuezhen Xue
- p53 Laboratory, 8A Biomedical Grove, Immunos #06-06, Singapore 138648, Singapore
| | - Chia-Yin Lee
- Singapore Immunology Network, 8A Biomedical Grove, Singapore 138648, Singapore
| | - Sarah Binte Zulkifli
- Institute of Medical Biology Microscopy Unit, 8A Biomedical Grove, Singapore 138648, Singapore
| | - Poh-Cheang Chiam
- p53 Laboratory, 8A Biomedical Grove, Immunos #06-06, Singapore 138648, Singapore
| | - Farid J Ghadessy
- p53 Laboratory, 8A Biomedical Grove, Immunos #06-06, Singapore 138648, Singapore
| | - David P Lane
- p53 Laboratory, 8A Biomedical Grove, Immunos #06-06, Singapore 138648, Singapore
| |
Collapse
|
|
45
|
Cardiac transcription factor Nkx2.5 interacts with p53 and modulates its activity. Arch Biochem Biophys 2015; 569:45-53. [DOI: 10.1016/j.abb.2015.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 02/01/2015] [Indexed: 01/30/2023]
|
|
46
|
Haghshenas B, Abdullah N, Nami Y, Radiah D, Rosli R, Khosroushahi AY. Different effects of two newly-isolated probiotic Lactobacillus plantarum 15HN and Lactococcus lactis subsp. Lactis 44Lac strains from traditional dairy products on cancer cell lines. Anaerobe 2014; 30:51-9. [PMID: 25168457 DOI: 10.1016/j.anaerobe.2014.08.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 07/22/2014] [Accepted: 08/18/2014] [Indexed: 01/04/2023]
|
|
47
|
Zhang B, Mehrotra S, Ng WL, Calvi BR. Low levels of p53 protein and chromatin silencing of p53 target genes repress apoptosis in Drosophila endocycling cells. PLoS Genet 2014; 10:e1004581. [PMID: 25211335 PMCID: PMC4161308 DOI: 10.1371/journal.pgen.1004581] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 07/03/2014] [Indexed: 12/23/2022] Open
Abstract
Apoptotic cell death is an important response to genotoxic stress that prevents oncogenesis. It is known that tissues can differ in their apoptotic response, but molecular mechanisms are little understood. Here, we show that Drosophila polyploid endocycling cells (G/S cycle) repress the apoptotic response to DNA damage through at least two mechanisms. First, the expression of all the Drosophila p53 protein isoforms is strongly repressed at a post-transcriptional step. Second, p53-regulated pro-apoptotic genes are epigenetically silenced in endocycling cells, preventing activation of a paused RNA Pol II by p53-dependent or p53-independent pathways. Over-expression of the p53A isoform did not activate this paused RNA Pol II complex in endocycling cells, but over-expression of the p53B isoform with a longer transactivation domain did, suggesting that dampened p53B protein levels are crucial for apoptotic repression. We also find that the p53A protein isoform is ubiquitinated and degraded by the proteasome in endocycling cells. In mitotic cycling cells, p53A was the only isoform expressed to detectable levels, and its mRNA and protein levels increased after irradiation, but there was no evidence for an increase in protein stability. However, our data suggest that p53A protein stability is regulated in unirradiated cells, which likely ensures that apoptosis does not occur in the absence of stress. Without irradiation, both p53A protein and a paused RNA pol II were pre-bound to the promoters of pro-apoptotic genes, preparing mitotic cycling cells for a rapid apoptotic response to genotoxic stress. Together, our results define molecular mechanisms by which different cells in development modulate their apoptotic response, with broader significance for the survival of normal and cancer polyploid cells in mammals. In order to maintain genome integrity, eukaryotic cells have evolved multiple ways to respond to DNA damage stress. One of the major cellular responses is apoptosis, during which the cell undergoes programmed cell death in order to prevent the propagation of the damaged genome to daughter cells. Although clinical observations and other studies have shown that tissues can differ in their apoptotic response, the molecular mechanisms underlying these differences are largely unknown. We have shown in our model system, Drosophila, that endocycling cells do not initiate cell death in response to DNA damage. The endocycle is a cell cycle variation that is widely found in nature and conserved from plant to animals. During the endocycle, cells duplicate their genomic DNA but do not enter mitosis to segregate chromosomes, resulting in a polyploid genome content. In this study, we investigate how the apoptotic response to DNA damage is repressed in endocycling cells. We find that the Drosophila ortholog of the human p53 tumor suppressor protein is expressed at very low levels in endocycling cells. Moreover, the downstream pro-apoptotic genes that are regulated by p53 are epigenetically silenced in endocycling cells. Our results provide important insights into tissue-specific apoptotic responses in development, with possible broader impact on understanding radiation therapy response and cancer of different tissues.
Collapse
Affiliation(s)
- Bingqing Zhang
- Department of Biology, Indiana University, Bloomington, Indiana, United States of America
| | - Sonam Mehrotra
- Department of Biology, Indiana University, Bloomington, Indiana, United States of America
| | - Wei Lun Ng
- Department of Biology, Indiana University, Bloomington, Indiana, United States of America
| | - Brian R. Calvi
- Department of Biology, Indiana University, Bloomington, Indiana, United States of America
- * E-mail:
| |
Collapse
|
|
48
|
Khoo KH, Hoe KK, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov 2014; 13:217-36. [PMID: 24577402 DOI: 10.1038/nrd4236] [Citation(s) in RCA: 568] [Impact Index Per Article: 51.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The tumour suppressor p53 is the most frequently mutated gene in human cancer, with more than half of all human tumours carrying mutations in this particular gene. Intense efforts to develop drugs that could activate or restore the p53 pathway have now reached clinical trials. The first clinical results with inhibitors of MDM2, a negative regulator of p53, have shown efficacy but hint at on-target toxicities. Here, we describe the current state of the development of p53 pathway modulators and new pathway targets that have emerged. The challenge of targeting protein-protein interactions and a fragile mutant transcription factor has stimulated many exciting new approaches to drug discovery.
Collapse
Affiliation(s)
| | - Khoo Kian Hoe
- p53 Laboratory (p53Lab), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06, Immunos, 138648 Singapore
| | - Chandra S Verma
- 1] Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street #07-01, Matrix, 138671 Singapore. [2] School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551 Singapore. [3] Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543 Singapore
| | - David P Lane
- p53 Laboratory (p53Lab), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06, Immunos, 138648 Singapore
| |
Collapse
|
|
49
|
Peptides genetically selected for NF-κB activation cooperate with oncogene Ras and model carcinogenic role of inflammation. Proc Natl Acad Sci U S A 2014; 111:E474-83. [PMID: 24474797 DOI: 10.1073/pnas.1311945111] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Chronic inflammation is associated with increased cancer risk. Furthermore, the transcription factor NF-κB, a central regulator of inflammatory responses, is constitutively active in most tumors. To determine whether active NF-κB inherently contributes to malignant transformation, we isolated a set of NF-κB-activating genetic elements and tested their oncogenic potential in rodent cell transformation models. Genetic elements with desired properties were isolated using biologically active selectable peptide technology, which involves functional screening of lentiviral libraries encoding 20 or 50 amino acid-long polypeptides supplemented with endoplasmic reticulum-targeting and oligomerization domains. Twelve NF-κB-activating selectable peptides (NASPs) representing specific fragments of six proteins, none of which was previously associated with NF-κB activation, were isolated from libraries of 200,000 peptides derived from 500 human extracellular proteins. Using selective knockdown of distinct components of the NF-κB pathway, we showed that the isolated NASPs act either via or upstream of TNF receptor-associated factor 6. Transduction of NASPs into mouse and rat embryo fibroblasts did not, in itself, alter their growth. However, when coexpressed with oncogenic Ras (H-Ras(V12)), NASPs allowed rodent fibroblasts to overcome H-Ras(V12)-mediated p53-dependent senescence and acquire a transformed tumorigenic phenotype. Consistent with their ability to cooperate with oncogenic Ras in cell transformation, NASP expression reduced the transactivation activity of p53. This system provides an in vitro model of NF-κB-driven carcinogenesis and suggests that the known carcinogenic effects of inflammation may be at least partially due to NF-κB-mediated abrogation of oncogene-induced senescence.
Collapse
|
|
50
|
The tumor suppressor p53 fine-tunes reactive oxygen species levels and neurogenesis via PI3 kinase signaling. J Neurosci 2013; 33:14318-30. [PMID: 24005285 DOI: 10.1523/jneurosci.1056-13.2013] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Mounting evidence points to a role for endogenous reactive oxygen species (ROS) in cell signaling, including in the control of cell proliferation, differentiation, and fate. However, the function of ROS and their molecular regulation in embryonic mouse neural progenitor cells (eNPCs) has not yet been clarified. Here, we describe that physiological ROS are required for appropriate timing of neurogenesis in the developing telencephalon in vivo and in cultured NPCs, and that the tumor suppressor p53 plays a key role in the regulation of ROS-dependent neurogenesis. p53 loss of function leads to elevated ROS and early neurogenesis, while restoration of p53 and antioxidant treatment partially reverse the phenotype associated with premature neurogenesis. Furthermore, we describe that the expression of a number of neurogenic and oxidative stress genes relies on p53 and that both p53 and ROS-dependent induction of neurogenesis depend on PI3 kinase/phospho-Akt signaling. Our results suggest that p53 fine-tunes endogenous ROS levels to ensure the appropriate timing of neurogenesis in eNPCs. This may also have implications for the generation of tumors of neurodevelopmental origin.
Collapse
|