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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Patil MR, Bihari A. A comprehensive study of p53 protein. J Cell Biochem 2022; 123:1891-1937. [PMID: 36183376 DOI: 10.1002/jcb.30331] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/02/2022] [Accepted: 09/13/2022] [Indexed: 01/10/2023]
Abstract
The protein p53 has been extensively investigated since it was found 43 years ago and has become a "guardian of the genome" that regulates the division of cells by preventing the growth of cells and dividing them, that is, inhibits the development of tumors. Initial proof of protein existence by researchers in the mid-1970s was found by altering and regulating the SV40 big T antigen termed the A protein. Researchers demonstrated how viruses play a role in cancer by employing viruses' ability to create T-antigens complex with viral tumors, which was discovered in 1979 following a viral analysis and cancer analog research. Researchers later in the year 1989 explained that in Murine Friend, a virus-caused erythroleukemia, commonly found that p53 was inactivated to suggest that p53 could be a "tumor suppressor gene." The TP53 gene, encoding p53, is one of human cancer's most frequently altered genes. The protein-regulated biological functions of all p53s include cell cycles, apoptosis, senescence, metabolism of the DNA, angiogenesis, cell differentiation, and immunological response. We tried to unfold the history of the p53 protein, which was discovered long back in 1979, that is, 43 years of research on p53, and how p53's function has been developed through time in this article.
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Affiliation(s)
- Manisha R Patil
- Department of Computer-Applications, School of Information Technology and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Anand Bihari
- Department of Computational Intelligence, School of Computer Science and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
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Over Fifty Years of Life, Death, and Cannibalism: A Historical Recollection of Apoptosis and Autophagy. Int J Mol Sci 2021; 22:ijms222212466. [PMID: 34830349 PMCID: PMC8618802 DOI: 10.3390/ijms222212466] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 01/18/2023] Open
Abstract
Research in biomedical sciences has changed dramatically over the past fifty years. There is no doubt that the discovery of apoptosis and autophagy as two highly synchronized and regulated mechanisms in cellular homeostasis are among the most important discoveries in these decades. Along with the advancement in molecular biology, identifying the genetic players in apoptosis and autophagy has shed light on our understanding of their function in physiological and pathological conditions. In this review, we first describe the history of key discoveries in apoptosis with a molecular insight and continue with apoptosis pathways and their regulation. We touch upon the role of apoptosis in human health and its malfunction in several diseases. We discuss the path to the morphological and molecular discovery of autophagy. Moreover, we dive deep into the precise regulation of autophagy and recent findings from basic research to clinical applications of autophagy modulation in human health and illnesses and the available therapies for many diseases caused by impaired autophagy. We conclude with the exciting crosstalk between apoptosis and autophagy, from the early discoveries to recent findings.
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Oren M. p53: not just a tumor suppressor. J Mol Cell Biol 2020; 11:539-543. [PMID: 31291648 PMCID: PMC6736137 DOI: 10.1093/jmcb/mjz070] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 06/26/2019] [Indexed: 02/07/2023] Open
Affiliation(s)
- Moshe Oren
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
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Sabapathy K, Lane DP. Understanding p53 functions through p53 antibodies. J Mol Cell Biol 2020; 11:317-329. [PMID: 30907951 PMCID: PMC6487784 DOI: 10.1093/jmcb/mjz010] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 01/20/2019] [Accepted: 02/11/2019] [Indexed: 01/19/2023] Open
Abstract
TP53 is the most frequently mutated gene across all cancer types. Our understanding of its functions has evolved since its discovery four decades ago. Initially thought to be an oncogene, it was later realized to be a critical tumour suppressor. A significant amount of our knowledge about p53 functions have come from the use of antibodies against its various forms. The early anti-p53 antibodies contributed to the recognition of p53 accumulation as a common feature of cancer cells and to our understanding of p53 DNA-binding and transcription activities. They led to the concept that conformational changes can facilitate p53’s activity as a growth inhibitory protein. The ensuing p53 conformational-specific antibodies further underlined p53’s conformational flexibility, collectively forming the basis for current efforts to generate therapeutic molecules capable of altering the conformation of mutant p53. A subsequent barrage of antibodies against post-translational modifications on p53 has clarified p53’s roles further, especially with respect to the mechanistic details and context-dependence of its activity. More recently, the generation of p53 mutation-specific antibodies have highlighted the possibility to go beyond the general framework of our comprehension of mutant p53—and promises to provide insights into the specific properties of individual p53 mutants. This review summarizes our current knowledge of p53 functions derived through the major classes of anti-p53 antibodies, which could be a paradigm for understanding other molecular events in health and disease.
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Affiliation(s)
- Kanaga Sabapathy
- Laboratory of Molecular Carcinogenesis, Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, Singapore.,Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, Singapore, Singapore.,Department of Biochemistry, National University of Singapore (NUS), 8 Medical Drive, Singapore, Singapore.,Institute of Molecular and Cellular Biology, 61 Biopolis Drive, Singapore, Singapore
| | - David P Lane
- p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
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6
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Weinberg RA. How TP53 (almost) became an oncogene. J Mol Cell Biol 2019; 11:531-533. [PMID: 31282927 PMCID: PMC6735798 DOI: 10.1093/jmcb/mjz061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 06/24/2019] [Indexed: 11/19/2022] Open
Affiliation(s)
- Robert A Weinberg
- Whitehead Institute for Biomedical Research, Ludwig/MIT Center for Molecular Oncology, MIT Department of Biology, Cambridge, MA 02142, USA
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Singh K, Dong Q, TimiriShanmugam PS, Koul S, Koul HK. Tetrandrine inhibits deregulated cell cycle in pancreatic cancer cells: Differential regulation of p21 Cip1/Waf1 , p27 Kip1 and cyclin D1. Cancer Lett 2018; 425:164-173. [DOI: 10.1016/j.canlet.2018.03.042] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/14/2018] [Accepted: 03/26/2018] [Indexed: 01/15/2023]
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Aloni-Grinstein R, Charni-Natan M, Solomon H, Rotter V. p53 and the Viral Connection: Back into the Future ‡. Cancers (Basel) 2018; 10:cancers10060178. [PMID: 29866997 PMCID: PMC6024945 DOI: 10.3390/cancers10060178] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 05/31/2018] [Accepted: 06/01/2018] [Indexed: 01/14/2023] Open
Abstract
The discovery of the tumor suppressor p53, through its interactions with proteins of tumor-promoting viruses, paved the way to the understanding of p53 roles in tumor virology. Over the years, accumulating data suggest that WTp53 is involved in the viral life cycle of non-tumor-promoting viruses as well. These include the influenza virus, smallpox and vaccinia viruses, the Zika virus, West Nile virus, Japanese encephalitis virus, Human Immunodeficiency Virus Type 1, Human herpes simplex virus-1, and more. Viruses have learned to manipulate WTp53 through different strategies to improve their replication and spreading in a stage-specific, bidirectional way. While some viruses require active WTp53 for efficient viral replication, others require reduction/inhibition of WTp53 activity. A better understanding of WTp53 functionality in viral life may offer new future clinical approaches, based on WTp53 manipulation, for viral infections.
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Affiliation(s)
- Ronit Aloni-Grinstein
- Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Box 19, 74100 Ness-Ziona, Israel.
| | - Meital Charni-Natan
- Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
| | - Hilla Solomon
- Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
| | - Varda Rotter
- Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
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MDM2-p53 Interactions in Human Hepatocellular Carcinoma: What Is the Role of Nutlins and New Therapeutic Options? J Clin Med 2018; 7:jcm7040064. [PMID: 29584707 PMCID: PMC5920438 DOI: 10.3390/jcm7040064] [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: 01/31/2018] [Revised: 03/22/2018] [Accepted: 03/23/2018] [Indexed: 12/18/2022] Open
Abstract
Human hepatocellular carcinoma (HCC) is the fifth most common cancer and is associated with poor prognosis worldwide. The molecular mechanisms underlying the pathogenesis of HCC have been an area of continuing interest, and recent studies using next generation sequencing (NGS) have revealed much regarding previously unsettled issues. Molecular studies using HCC samples have been mainly targeted with the aim to identify the fundamental mechanisms contributing to HCC and identify more effective treatments. In response to cellular stresses (e.g., DNA damage or oncogenes), activated p53 elicits appropriate responses that aim at DNA repair, genetic stability, cell cycle arrest, and the deletion of DNA-damaged cells. On the other hand, the murine double minute 2 (MDM2) oncogene protein is an important cellular antagonist of p53. MDM2 negatively regulates p53 activity through the induction of p53 protein degradation. However, current research has shown that the mechanisms underlying MDM2-p53 interactions are more complex than previously thought. Microarray data have added new insight into the transcription changes in HCC. Recently, Nutlin-3 has shown potency against p53-MDM2 binding and the enhancement of p53 stabilization as well as an increment of p53 cellular accumulation with potential therapeutic effects. This review outlines the molecular mechanisms involved in the p53-MDM2 pathways, the biological factors influencing these pathways, and their roles in the pathogenesis of HCC. It also discusses the action of Nutlin-3 treatment in inducing growth arrest in HCC and elaborates on future directions in research in this area. More research on the biology of p53-MDM2 interactions may offer a better understanding of these mechanisms and discover new biomarkers, sensitive prognostic indicators as well as new therapeutic interventions in HCC.
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Guedes LB, Almutairi F, Haffner MC, Rajoria G, Liu Z, Klimek S, Zoino R, Yousefi K, Sharma R, De Marzo AM, Netto GJ, Isaacs WB, Ross AE, Schaeffer EM, Lotan TL. Analytic, Preanalytic, and Clinical Validation of p53 IHC for Detection of TP53 Missense Mutation in Prostate Cancer. Clin Cancer Res 2017; 23:4693-4703. [PMID: 28446506 PMCID: PMC5559307 DOI: 10.1158/1078-0432.ccr-17-0257] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 03/14/2017] [Accepted: 04/21/2017] [Indexed: 01/12/2023]
Abstract
Purpose:TP53 missense mutations may help to identify prostate cancer with lethal potential. Here, we preanalytically, analytically, and clinically validated a robust IHC assay to detect subclonal and focal TP53 missense mutations in prostate cancer.Experimental Design: The p53 IHC assay was performed in a CLIA-accredited laboratory on the Ventana Benchmark immunostaining system. p53 protein nuclear accumulation was defined as any p53 nuclear labeling in >10% of tumor cells. Fifty-four formalin-fixed paraffin embedded (FFPE) cell lines from the NCI-60 panel and 103 FFPE prostate cancer tissues (88 primary adenocarcinomas, 15 metastases) with known TP53 mutation status were studied. DU145 and VCaP xenografts were subjected to varying fixation conditions to investigate the effects of preanalytic variables. Clinical validation was performed in two partially overlapping radical prostatectomy cohorts.Results: p53 nuclear accumulation by IHC was 100% sensitive for detection of TP53 missense mutations in the NCI-60 panel (25/25 missense mutations correctly identified). Lack of p53 nuclear accumulation was 86% (25/29) specific for absence of TP53 missense mutation. In FFPE prostate tumors, the positive predictive value of p53 nuclear accumulation for underlying missense mutation was 84% (38/45), whereas the negative predictive value was 97% (56/58). In a cohort of men who experienced biochemical recurrence after RP, the multivariable HR for metastasis among cases with p53 nuclear accumulation compared with those without was 2.55 (95% confidence interval, 1.1-5.91).Conclusions: IHC is widely available method to assess for the presence of deleterious and heterogeneous TP53 missense mutations in clinical prostate cancer specimens. Clin Cancer Res; 23(16); 4693-703. ©2017 AACR.
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Affiliation(s)
- Liana B Guedes
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Fawaz Almutairi
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michael C Haffner
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Zach Liu
- Pathline Emerge Pathology Services, Ramsey, New Jersey
| | | | - Roberto Zoino
- Pathline Emerge Pathology Services, Ramsey, New Jersey
| | | | - Rajni Sharma
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Angelo M De Marzo
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - George J Netto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - William B Isaacs
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ashley E Ross
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Edward M Schaeffer
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Tamara L Lotan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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11
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Abstract
PURPOSE OF REVIEW The p53 tumor suppressor is a master regulator of antitumor defenses through its control of growth arrest, senescence and apoptosis. In recent years, p53 regulation was found to extend to a variety of biological processes including autophagy, fertility, metabolism and immune responses. Here, we focus on the role of p53 in the immune system. We explore the relationship between p53 and the innate immune response with particular emphasis on the Toll-like receptor (TLR) pathway and implications for cancer therapy. RECENT FINDINGS Numerous studies have shown that the immune system, especially innate immunity, has a critical role in tumor development. It appears that p53 can influence innate immune responses as part of its tumor suppressor activities and recent work suggests that the complete set of innate immune TLR genes are responsive to chromosomal stress and the transcriptional network regulated by p53. Activation of p53 by common antitumor agents results in p53 dependent regulation of expression of most TLR genes in human primary and cancer cell lines, resulting in modulation of TLR downstream responses to cognate ligands. In addition several tumor-associated p53 mutants can also affect TLR gene expression. These observations together with the discovery of other immune-related p53 target genes provide new insights into the relationship between p53 and immunity and suggest approaches that might be useful in cancer therapies. SUMMARY The tumor suppressor p53 can modulate innate immune gene responses in response to factors that can activate p53. This is expected to provide new opportunities in cancer diagnosis and in chemotherapeutic strategies that employ specific TLR agonists or antagonists that target the TLR pathway.
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Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Genes Cancer 2011; 2:466-74. [PMID: 21779514 DOI: 10.1177/1947601911408889] [Citation(s) in RCA: 687] [Impact Index Per Article: 49.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Inactivation of the p53 tumor suppressor is a frequent event in tumorigenesis. In most cases, the p53 gene is mutated, giving rise to a stable mutant protein whose accumulation is regarded as a hallmark of cancer cells. Mutant p53 proteins not only lose their tumor suppressive activities but often gain additional oncogenic functions that endow cells with growth and survival advantages. Interestingly, mutations in the p53 gene were shown to occur at different phases of the multistep process of malignant transformation, thus contributing differentially to tumor initiation, promotion, aggressiveness, and metastasis. Here, the authors review the different studies on the involvement of p53 inactivation at various stages of tumorigenesis and highlight the specific contribution of p53 mutations at each phase of cancer progression.
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Affiliation(s)
- Noa Rivlin
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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Galluzzi L, Morselli E, Kepp O, Vitale I, Pinti M, Kroemer G. Mitochondrial liaisons of p53. Antioxid Redox Signal 2011; 15:1691-714. [PMID: 20712408 DOI: 10.1089/ars.2010.3504] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Mitochondria play a central role in cell survival and cell death. While producing the bulk of intracellular ATP, mitochondrial respiration represents the most prominent source of harmful reactive oxygen species. Mitochondria participate in many anabolic pathways, including cholesterol and nucleotide biosynthesis, yet also control multiple biochemical cascades that contribute to the programmed demise of cells. The tumor suppressor protein p53 is best known for its ability to orchestrate a transcriptional response to stress that can have multiple outcomes, including cell cycle arrest and cell death. p53-mediated tumor suppression, however, also involves transcription-independent mechanisms. Cytoplasmic p53 can physically interact with members of the BCL-2 protein family, thereby promoting mitochondrial membrane permeabilization. Moreover, extranuclear p53 can suppress autophagy, a major prosurvival mechanism that is activated in response to multiple stress conditions. Thirty years have passed since its discovery, and p53 has been ascribed with an ever-increasing number of functions. For instance, p53 has turned out to influence the cell's redox status, by transactivating either anti- or pro-oxidant factors, and to regulate the metabolic switch between glycolysis and aerobic respiration. In this review, we will analyze the mechanisms by which p53 affects the balance between the vital and lethal functions of mitochondria.
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Affiliation(s)
- Lorenzo Galluzzi
- INSERM U848, Institut Gustave Roussy, Pavillon de Recherche 1, Villejuif (Paris), France
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14
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Lane D, Levine A. p53 Research: the past thirty years and the next thirty years. Cold Spring Harb Perspect Biol 2010; 2:a000893. [PMID: 20463001 DOI: 10.1101/cshperspect.a000893] [Citation(s) in RCA: 312] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Thirty years of research on the p53 family of genes has generated almost fifty thousand publications. The first of these papers detected the p53 protein associated with a viral oncogene product in transformed cells and tumors and focused the field on cancer biology. Subsequent manuscripts have shown a wide variety of functions for the p53 family of genes and their proteins. These proteins are involved in reproduction, genomic repair, fidelity and recombination, the regulation of metabolic processes, longevity, surveillance of the stability of development, the production of stem cells and changes in epigenetic marks, the development of the nervous system (p73), the immune system (p73) and skin (p63), as well as the better known roles for the family in tumor suppression. The p53 family of genes has been found in the modern day ancestors of organisms with over one billion years of evolutionary history where they play a role in germ-line fidelity over that time span. As the body plan of the vertebrates emerged with the regeneration of tissues by stem cells over a lifetime, the p53 gene and its protein were adapted to be a tumor suppressor of somatic stem and progenitor cells complementing its' past functions in the germ line. Because the p53 family of genes has played a role in germ-line fidelity and preservation of the species, even in times of stress, these genes have been under constant selection pressure to change and adapt to new situations. This has given rise to this diversity of functions all working to preserve homeostatic processes that permit growth and reproduction in a world that is constantly challenging the fidelity of information transfer at each generation. The p53 family of gene products has influenced the rates of evolutionary change, just as evolutionary changes have altered the p53 family and its functions.
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Affiliation(s)
- David Lane
- p53 Laboratory (A-Star) 8A Biomedical Grove Immunos Singapore 138648
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15
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Abstract
Thirty years ago p53 was discovered as a cellular partner of simian virus 40 large T-antigen, the oncoprotein of this tumour virus. The first decade of p53 research saw the cloning of p53 DNA and the realization that p53 is not an oncogene but a tumour suppressor that is very frequently mutated in human cancer. In the second decade of research, the function of p53 was uncovered: it is a transcription factor induced by stress, which can promote cell cycle arrest, apoptosis and senescence. In the third decade after its discovery new functions of this protein were revealed, including the regulation of metabolic pathways and cytokines that are required for embryo implantation. The fourth decade of research may see new p53-based drugs to treat cancer. What is next is anybody's guess.
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Affiliation(s)
- Arnold J Levine
- Arnold J. Levine is at the Institute for Advanced Study, School of Natural Sciences, Einstein Drive, Princeton, New Jersey 08540, USA.
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16
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Abstract
Ample data indicate that mutant p53 proteins not only lose their tumour suppressive functions, but also gain new abilities that promote tumorigenesis. Moreover, recent studies have modified our view of mutant p53 proteins, portraying them not as inert mutants, but rather as regulated proteins that influence the cancer cell transcriptome and phenotype. This influence is clinically manifested as association of TP53 mutations with poor prognosis and drug resistance in a growing array of malignancies. Here, we review recent studies on mutant p53 regulation, gain-of-function mechanisms, transcriptional effects and prognostic association, with a focus on the clinical implications of these findings.
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Affiliation(s)
- Ran Brosh
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
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17
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Abstract
Among the 278,092 publications indexed into PubMed in 1979, a handful of articles stand out as the foundation of one of the most profound forays into the molecular basis of carcinogenesis: the discovery of the p53 tumour-suppressor protein. In the 30 years since then, understanding of p53 has progressed from obscure oncogene to key tumour-suppressor gene with clinical potential. Yet, p53 research has not followed a straight course. In this Historical Review, we describe how the 1979 discovery has shaped our view of the molecular basis of cancer, and identify some crucial steps ahead to transfer the wealth of knowledge accumulated on p53 into applications to cancer prevention and treatment.
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Madar S, Goldstein I, Rotter V. Did Experimental Biology Die? Lessons from 30 Years of p53 Research. Cancer Res 2009; 69:6378-80. [DOI: 10.1158/0008-5472.can-09-0940] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Belousov PV, Kuprash DV, Sazykin AY, Khlgatian SV, Penkov DN, Shebzukhov YV, Nedospasov SA. Cancer-associated antigens and antigen arrays in serological diagnostics of malignant tumors. BIOCHEMISTRY (MOSCOW) 2008; 73:562-72. [PMID: 18605981 DOI: 10.1134/s000629790805009x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The appearance of antibodies to cancer-associated antigens in biological fluids (particularly, in blood sera) of cancer patients is now a well-established fact, and their detection by immunochemical methods is a promising approach to diagnostics of malignant neoplasms. In this review, we consider some immunobiological aspects of the most extensively studied cancer-associated B-cell antigens, various applications of autoantibodies as cancer biomarkers, and prospects for the use of antigen arrays for improving diagnostic sensitivity.
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Affiliation(s)
- P V Belousov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
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20
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Kurth R. The functional significance of tumour-associated cell surface alterations of embryonic and unknown origin. CIBA FOUNDATION SYMPOSIUM 2008; 96:104-24. [PMID: 6343000 DOI: 10.1002/9780470720776.ch7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The study of the phenotype of tumours aims to elucidate cell surface alterations that could be used for diagnostic, prognostic or therapeutic purposes. As tumours tend to escape the homeostatic growth control mechanisms of the host, it can be assumed that plasma membrane alterations are also responsible for the antisocial behaviour of tumour cells. Selected features of the transformed phenotype, of fetal or unknown origin, namely tumour-associated antigens, isozymes and growth factors, are discussed in relation to the altered growth pattern of the tumour cell. It is concluded that definitive structure-function relationships have not yet been established, but areas for future investigation are suggested.
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Abstract
In addition to the loss of wild-type p53 activity, a high percentage of tumor cells accumulate mutant p53 protein isoforms. Whereas the hallmark of the wild-type p53 is its tumor suppressor activities, tumor-associated mutant p53 proteins acquire novel functions enabling them to promote a large spectrum of cancer phenotypes. During the last years, it became clear that tumor-associated mutant p53 proteins are not only distinct from the wild-type p53, but they also represent a heterogeneous population of proteins with a variety of structure-function features. One of the major mechanisms underlying mutant p53 gain of function is the ability to regulate gene expression. Although a large number of specific target genes were identified, the molecular basis for this regulation is not fully elucidated. This review describes the present knowledge about the transcriptional activities of mutant p53 and the mechanisms that might underlie its target gene specificity.
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Affiliation(s)
- L Weisz
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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22
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Gomez-Lazaro M, Fernandez-Gomez FJ, Jordán J. p53: Twenty five years understanding the mechanism of genome protection. J Physiol Biochem 2004; 60:287-307. [PMID: 15957248 DOI: 10.1007/bf03167075] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
This year the p53 protein, also known as "guardian of the genome", turns twenty five years old. During this period the p53 knowledge have changed from an initial pro-oncogene activity to the tumorsupressor p53 function. p53 is activated upon stress signals, such as gamma irradiation, UV, hypoxia, virus infection, and DNA damage, leading to protection of cells by inducing target genes. The molecules activated by p53 induce cell cycle arrest, DNA repair to conserve the genome and apoptosis. The regulation of p53 functions is tightly controlled through several mechanisms including p53 transcription and translation, protein stability, post-translational modifications, and subcellular localization. In fact, mutations in p53 are the most frequent molecular alterations detected in human tumours. Furthermore, in some degenerative processes, fragmentation and oxidative damage in DNA take place, and in these situations p53 is involved. So, p53 is considered a pharmacological target, p53 overexpression induces apoptosis in cancer and its expression blockage protects cells against lethal insults.
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Affiliation(s)
- M Gomez-Lazaro
- Centro Regional de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Castilla-La Mancha, Avda. Almansa, 02006 Albacete, Spain
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23
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May P, May E. Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene 1999; 18:7621-36. [PMID: 10618702 DOI: 10.1038/sj.onc.1203285] [Citation(s) in RCA: 438] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- P May
- Laboratoire de Cancérogenèse Moléculaire, UMR 217 CEA-CNRS, DRR, DSV, CEA 60-68 Av. Division Leclerc B.P. no 6-92265 Fontenay Aux Roses Cedex, France
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24
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Selter H, Schmidt G, Villena-Heinsen C, Montenarh M. Humoral immune response to p21WAF1/CIP1 in tumor patients, non-tumorous patients and healthy blood donors. Cancer Lett 1999; 137:151-7. [PMID: 10374836 DOI: 10.1016/s0304-3835(98)00356-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
We performed a serological analysis for anti-p21WAF1/CIP1 antibodies in sera of patients with different gynecological diseases such as breast cancer, ovarian carcinoma, cervix carcinoma and benign gynecological tissue alterations and from healthy blood donors using the immunoblotting technique with recombinant p21WAF1/CIP1 as antigen as well as a newly designed ELISA. We detected antibodies specific for p21WAF1/CIP1 in sera derived from cancer patients, as well as from patients with non-malignant diseases and from healthy blood donors. Thus, the presence of antibodies against p21WAF1/CIP1 is not a marker for malignancies. Some of the sera with antibodies against p21WAF1/CIP1 also contained antibodies against the oncoprotein mdm2, and/or the growth suppressor gene product p53. The presence of antibodies against p53 correlates with a malignant disease.
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Affiliation(s)
- H Selter
- Medical Biochemistry and Molecular Biology, University of the Saarland, Homburg, Germany
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25
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Almog N, Rotter V. Involvement of p53 in cell differentiation and development. BIOCHIMICA ET BIOPHYSICA ACTA 1997; 1333:F1-27. [PMID: 9294016 DOI: 10.1016/s0304-419x(97)00012-7] [Citation(s) in RCA: 66] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- N Almog
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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26
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Selter H, Amela-Neuschwander S, Villena-Heinsen C, Montenarh M. Antibodies against murine double minute-2 (mdm2) in sera of patients with various gynaecological diseases. Cancer Lett 1995; 96:111-5. [PMID: 7553598 DOI: 10.1016/0304-3835(95)03920-r] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We performed a serologic analysis for anti-murine double minute-2 (anti-mdm2) antibodies in sera of patients with different gynaecological diseases using immunoblotting technique with recombinant mdm2 as antigen. In addition, for large scale screening we established an anti-mdm2 enzyme-linked immunosorbent assay (ELISA). Serum samples from patients with breast cancer, ovarian carcinoma, cervix carcinoma and benign gynaecological tissue alterations were tested. We detected antibodies specific for mdm2 in sera derived from cancer patients, as well as from patients with non-malignant diseases. Some of the sera with antibodies against mdm2 also contained antibodies against the growth suppressor gene product p53.
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Affiliation(s)
- H Selter
- Institute of Medical Biochemistry, University of the Saarland, Homburg, Germany
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27
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Sebag M, Gulliver W, Kremer R. Effect of 1,25 dihydroxyvitamin D3 and calcium on growth and differentiation and on c-fos and p53 gene expression in normal human keratinocytes. J Invest Dermatol 1994; 103:323-9. [PMID: 8077697 DOI: 10.1111/1523-1747.ep12394802] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Calcium enhances keratinocyte differentiation, and 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) is both antiproliferative and prodifferentiative in many cell types, including normal human keratinocytes. In the present study, we examined the combined effects of calcium and 1,25(OH)2D3 on parameters of growth and differentiation and on c-fos and p53 gene expression in normal human keratinocytes. Exposure of normal human keratinocytes to 1,25(OH)2D3 markedly reduced [3H] thymidine incorporation and cell number at low and high medium Ca++ concentrations. Simultaneously, cells in the G0/G1 phase of the cell cycle increased significantly and those in the S phase fell precipitously. 1,25(OH)2D3 and calcium also induced keratinocyte differentiation independently, as assessed by immunocytochemistry and by induction of involucrin mRNA. Both Ca++ and 1,25(OH)2D3 were shown, by nuclear run-on assays, to increase involucrin gene transcription. A rapid, transient elevation in c-fos protooncogene expression preceded these effects when epidermal growth factor was present alone. When 1,25(OH)2D3 was added to quiescent keratinocytes, there was a marked augmentation of c-fos mRNA accumulation at low and high medium Ca++ concentrations. Varying medium Ca++ concentrations had no effect on c-fos mRNA levels. Increasing medium Ca++ concentrations from 0.15 to 2.0 mM produced marked elevations of p53 mRNA accumulation and of the rate of p53 gene transcription, whereas 1,25(OH)2D3 had no effect. These results, therefore, suggest that 1,25(OH)2D3 and calcium act in concert to modulate the expression of two important cell-cycle-associated genes, which may be important components in the initial programming of growth and differentiation of normal human keratinocytes.
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Affiliation(s)
- M Sebag
- Department of Medicine, McGill University, Montreal, Quebec, Canada
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28
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Tiemann F, Deppert W. Stabilization of the tumor suppressor p53 during cellular transformation by simian virus 40: influence of viral and cellular factors and biological consequences. J Virol 1994; 68:2869-78. [PMID: 8151757 PMCID: PMC236775 DOI: 10.1128/jvi.68.5.2869-2878.1994] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
To understand the process and biological significance of metabolic stabilization of p53 during simian virus 40 (SV40)-induced cellular transformation, we analyzed cellular and viral parameters involved in this process. We demonstrate that neither large T expression as such nor the cellular phenotype (normal versus transformed) markedly influence the stability of p53 complexed to large T in SV40 abortively infected BALB/c mouse fibroblasts. In contrast, metabolic stabilization of p53 is an active cellular event, specifically induced by SV40. The ability of SV40 to induce a cellular response leading to stabilization of p53 complexed to large T is independent from the cellular phenotype and greatly varies between different cells. However, metabolic stability was conferred only to p53 in complex with large T, whereas the free p53 in these cells remained metabolically unstable. Comparative analyses of cellular transformation in various cells differing in stability of p53 complexed to large T upon abortive infection with SV40 revealed a strong correlation between the ability of SV40 to induce metabolic stabilization and its transformation efficiency. Our data suggest that metabolic stabilization and the ensuing enhanced levels of p53 are important for initiation and/or maintenance of SV40 transformation.
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Affiliation(s)
- F Tiemann
- Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Universität Hamburg, Germany
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29
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Soussi T, Legros Y, Lubin R, Ory K, Schlichtholz B. Multifactorial analysis of p53 alteration in human cancer: a review. Int J Cancer 1994; 57:1-9. [PMID: 8150526 DOI: 10.1002/ijc.2910570102] [Citation(s) in RCA: 248] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- T Soussi
- Unité 301 INSERM, Institut de Génétique Moléculaire, Paris, France
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30
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Jabs DA, Prendergast RA. Murine models of Sjögren's syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 1994; 350:623-30. [PMID: 8030545 DOI: 10.1007/978-1-4615-2417-5_104] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Autoimmune MRL/lpr, MRL/+, and NZB/W mice all develop lacrimal gland inflammatory lesions, which consist of focal mononuclear inflammatory cell infiltrates. Each strain has a different immunocytochemical profile, which appears to be related to the underlying immunologic defects present in that mouse. The appearance of these lesions parallels the evolution of the systemic autoimmune disease. The lesions are dynamic over time with the early appearance of CD4+ T cells (helper T cells) for each strain. Subsequently, there is an accumulation of B cells over time in MRL/+ and NZB/W mice. In the two more rapidly evolving mouse models, MRL/lpr and NZB/W, there is a progressive decline in the percentage of CD8+ cells. Conversely, in the slowly evolving MRL/+ lacrimal gland lesions, there is a persistent and unchanging percentage of CD8+ T cells (suppressor/cytotoxic T cells). Autoimmune mice provide models for the human disorder Sjögren's syndrome and a mechanism for better understanding the immunopathogenesis of autoimmune lacrimal gland disease.
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Affiliation(s)
- D A Jabs
- Wilmer Ophthalmological Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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31
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Milne DM, Palmer RH, Meek DW. Mutation of the casein kinase II phosphorylation site abolishes the anti-proliferative activity of p53. Nucleic Acids Res 1992; 20:5565-70. [PMID: 1454521 PMCID: PMC334387 DOI: 10.1093/nar/20.21.5565] [Citation(s) in RCA: 91] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The p53 tumour suppressor protein is phosphorylated by several protein kinases, including casein kinase II. In order to understand the functional significance of phosphorylation by casein kinase II, we have introduced mutations at serine 386 in mouse p53, the residue phosphorylated by this kinase, and investigated their effects on the ability of p53 to arrest cell growth. Replacement of serine 386 by alanine led to loss of growth suppressor activity, while aspartic acid at this position partially retained suppressor function. These data suggest that the anti-proliferative activity of p53 is activated by phosphorylation at serine 386, and establish a direct link between the covalent modification of a growth suppressor protein and regulation of its activity in mammalian cells.
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Affiliation(s)
- D M Milne
- Department of Biochemistry, University of Dundee, UK
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32
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Gjerset RA, Arya J, Volkman S, Haas M. Association of induction of a fully tumorigenic phenotype in murine radiation-induced T-lymphoma cells with loss of differentiation antigens, gain of CD44, and alterations in p53 protein levels. Mol Carcinog 1992; 5:190-8. [PMID: 1586448 DOI: 10.1002/mc.2940050305] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We investigated the mechanism of radiation induction of murine thymic lymphomas by studying the characteristics of primary x-ray-induced thymic lymphoma (PXTL) cell lines and of their oncogene-induced, progressed progeny. It is widely thought that proto-oncogene alterations are associated with the induction of murine lymphomas; however, few, if any primary murine radiation-induced lymphomas possess (proto-)oncogene alterations. Independently derived cell lines grown directly (i.e., without in vivo transplantation) from thymic lymphomas of irradiated C57BL/6 mice possess the properties of immortalized pre-T cells and lack many of the characteristics of "tumor cells". PXTL cells are poorly tumorigenic upon transplantation, do not clone in methylcellulose cultures, are growth factor dependent and autocrine, and lack consistent chromosome and oncogene abnormalities. However, the thymic lymphomas are malignant and cause the death of each afflicted mouse. PXTL cells expressed two immunologically distinct forms of the tumor suppressor protein p53 that have moderately increased stability (t1/2 = 1 h) when compared with p53 of normal splenic T lymphocytes. Early PXTL cells could progress in vitro to a fully tumorigenic phenotype after infection with retroviruses encoding the c-myc and v-ras oncogenes. Progressed T-lymphoma cells acquired growth factor independence, a highly transplantable and tumorigenic phenotype, and the ability to quantitatively clone in methylcellulose cultures. Progressed lymphoma cells coordinately downregulated the expression of five T-cell differentiation markers, upregulated the expression of CD44 (Pgp-1), and harbored vastly elevated levels of two immunologically distinct forms of p53. Our results suggest that the early thymic lymphomas consist of differentiation-inhibited, immortal pre-T cells that are precursors to progressed, fully tumorigenic T-lymphoma cells.
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Affiliation(s)
- R A Gjerset
- UCSD Cancer Center, University of California, San Diego, La Jolla 92093-0063
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33
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Foord OS, Bhattacharya P, Reich Z, Rotter V. A DNA binding domain is contained in the C-terminus of wild type p53 protein. Nucleic Acids Res 1991; 19:5191-8. [PMID: 1923804 PMCID: PMC328875 DOI: 10.1093/nar/19.19.5191] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
In the present study we evaluated the DNA binding activity of wild type and mutant p53 proteins that were isolated from bacterial expression vectors. A comparison of the binding activities of the various purified p53 proteins, assessed by their ability to bind DNA cellulose columns, indicated that wild type p53 has a higher affinity to DNA than have mutant p53 forms. Furthermore, only wild type p53 was able to bind genomic DNA upon electrophoretic protein blotting. As specific deletion of the C-terminal region of wild type p53 totally abolished binding to genomic DNA, it was concluded that the 47 C-terminal amino acids contain the DNA binding region. The fact that the N-terminus contains a transcription activation region whereas the C-terminus contains a DNA binding domain places p53 in the family of typical transcription factors. Our experiments show that the topographical positioning of these domains plays an important role in the activity of wild type p53.
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Affiliation(s)
- O S Foord
- Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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34
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Michael-Michalovitz D, Yehiely F, Gottlieb E, Oren M. Simian virus 40 can overcome the antiproliferative effect of wild-type p53 in the absence of stable large T antigen-p53 binding. J Virol 1991; 65:4160-8. [PMID: 1649323 PMCID: PMC248850 DOI: 10.1128/jvi.65.8.4160-4168.1991] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
In simian virus 40 (SV40)-transformed cells, a tight complex is formed between the viral large T antigen (large T) and p53. It has been proposed that this complex interferes with the antiproliferative activity of p53. This notion was tested in primary rat fibroblasts by assessing the ability of SV40-mediated transformation to be spared from the inhibitory effect of wild-type (wt) p53. The data indicate that relative to transformation induced by myc plus ras, SV40-plus-ras-mediated focus formation was indeed much less suppressed by p53 plasmids. A majority of the resultant cell lines made a p53 protein with properties characteristic of a wt conformation. Furthermore, cell lines expressing stably both SV40 large T and a temperature-sensitive p53 mutant continued to proliferate at a temperature at which this p53 assumes wt-like properties and normally causes a growth arrest. Surprisingly, at least partial resistance to the growth-inhibitory effect of wt p53 was also evident when transformation was mediated by an SV40 deletion mutant, encoding a large T which does not bind p53 detectably. In addition to supporting the idea that SV40 can overcome the growth-restrictive activity of wt p53, these findings strongly suggest that at least part of this effect does not require a stable association between p53 and large T.
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35
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Prohibitin, an evolutionarily conserved intracellular protein that blocks DNA synthesis in normal fibroblasts and HeLa cells. Mol Cell Biol 1991. [PMID: 1996099 DOI: 10.1128/mcb.11.3.1372] [Citation(s) in RCA: 161] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Genes that act inside the cell to negatively regulate proliferation are of great interest because of their implications for such processes as development and cancer, but these genes have been difficult to clone. This report details the cloning and analysis of cDNA for prohibitin, a novel mammalian antiproliferative protein. Microinjection of synthetic prohibitin mRNA blocks entry into S phase in both normal fibroblasts and HeLa cells. Microinjection of an antisense oligonucleotide stimulates entry into S phase. By sequence comparison, the prohibitin gene appears to be the mammalian analog of Cc, a Drosophila gene that is vital for normal development.
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36
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Prohibitin, an evolutionarily conserved intracellular protein that blocks DNA synthesis in normal fibroblasts and HeLa cells. Mol Cell Biol 1991; 11:1372-81. [PMID: 1996099 PMCID: PMC369408 DOI: 10.1128/mcb.11.3.1372-1381.1991] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Genes that act inside the cell to negatively regulate proliferation are of great interest because of their implications for such processes as development and cancer, but these genes have been difficult to clone. This report details the cloning and analysis of cDNA for prohibitin, a novel mammalian antiproliferative protein. Microinjection of synthetic prohibitin mRNA blocks entry into S phase in both normal fibroblasts and HeLa cells. Microinjection of an antisense oligonucleotide stimulates entry into S phase. By sequence comparison, the prohibitin gene appears to be the mammalian analog of Cc, a Drosophila gene that is vital for normal development.
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37
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Expression of wild-type p53 is not compatible with continued growth of p53-negative tumor cells. Mol Cell Biol 1991. [PMID: 1986214 DOI: 10.1128/mcb.11.1.1] [Citation(s) in RCA: 66] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Inactivation of the cellular p53 gene is a common feature of Friend virus-induced murine erythroleukemia cell lines and may represent a necessary step in the progression of this disease. As well, frequent loss or mutation of p53 alleles in diverse human tumors is consistent with the view of p53 as a tumor suppressor gene. To examine the significance of p53 gene inactivation in tumorigenesis, we have attempted to express transfected wild-type p53 in three p53-negative tumor cell lines: murine DP16-1 Friend erythroleukemia cells, human K562 cells, and SKOV-3 cells. We found that aberrant p53 proteins, which differ from wild-type p53 by a single amino acid substitution, were expressed stably in these cells, whereas wild-type p53 expression was not tolerated. The inability of p53-negative tumor cell lines to support long-term expression of wild-type p53 protein is consistent with the view that p53 is a tumor suppressor gene.
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38
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Abstract
It has been suggested that the dominant effect of mutant p53 on tumor progression may reflect the mutant protein binding to wild-type p53, with inactivation of suppressor function. To date, evidence for wild-type/mutant p53 complexes involves p53 from different species. To investigate wild-type/mutant p53 complexes in relation to natural tumor progression, we sought to identify intraspecific complexes, using murine p53. The mutant phenotype p53-246(0) was used because this phenotype is immunologically distinct from wild-type p53-246+ and thus permits immunological analysis for wild-type/mutant p53 complexes. The p53 proteins were derived from genetically defined p53 cDNAs expressed in vitro and also from phenotypic variants of p53 expressed in vivo. We found that the mutant p53 phenotype was able to form a complex with the wild type when the two p53 variants were cotranslated. When mixed in their native states (after translation), the wild-type and mutant p53 proteins did not exhibit any binding affinity for each other in vitro. Under identical conditions, complexes of wild-type human and murine p53 proteins were formed. For murine p53, both the wild-type and mutant p53 proteins formed high-molecular-weight complexes when translated in vitro. This oligomerization appeared to involve the carboxyl terminus, since truncated p53 (amino acids 1 to 343) did not form complexes. We suggest that the ability of the mutant p53 phenotype to complex with wild type during cotranslation may contribute to the transforming function of activated mutants of p53 in vivo.
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39
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Expression of wild-type p53 is not compatible with continued growth of p53-negative tumor cells. Mol Cell Biol 1991; 11:1-11. [PMID: 1986214 PMCID: PMC359576 DOI: 10.1128/mcb.11.1.1-11.1991] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Inactivation of the cellular p53 gene is a common feature of Friend virus-induced murine erythroleukemia cell lines and may represent a necessary step in the progression of this disease. As well, frequent loss or mutation of p53 alleles in diverse human tumors is consistent with the view of p53 as a tumor suppressor gene. To examine the significance of p53 gene inactivation in tumorigenesis, we have attempted to express transfected wild-type p53 in three p53-negative tumor cell lines: murine DP16-1 Friend erythroleukemia cells, human K562 cells, and SKOV-3 cells. We found that aberrant p53 proteins, which differ from wild-type p53 by a single amino acid substitution, were expressed stably in these cells, whereas wild-type p53 expression was not tolerated. The inability of p53-negative tumor cell lines to support long-term expression of wild-type p53 protein is consistent with the view that p53 is a tumor suppressor gene.
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40
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Abstract
It has been suggested that the dominant effect of mutant p53 on tumor progression may reflect the mutant protein binding to wild-type p53, with inactivation of suppressor function. To date, evidence for wild-type/mutant p53 complexes involves p53 from different species. To investigate wild-type/mutant p53 complexes in relation to natural tumor progression, we sought to identify intraspecific complexes, using murine p53. The mutant phenotype p53-246(0) was used because this phenotype is immunologically distinct from wild-type p53-246+ and thus permits immunological analysis for wild-type/mutant p53 complexes. The p53 proteins were derived from genetically defined p53 cDNAs expressed in vitro and also from phenotypic variants of p53 expressed in vivo. We found that the mutant p53 phenotype was able to form a complex with the wild type when the two p53 variants were cotranslated. When mixed in their native states (after translation), the wild-type and mutant p53 proteins did not exhibit any binding affinity for each other in vitro. Under identical conditions, complexes of wild-type human and murine p53 proteins were formed. For murine p53, both the wild-type and mutant p53 proteins formed high-molecular-weight complexes when translated in vitro. This oligomerization appeared to involve the carboxyl terminus, since truncated p53 (amino acids 1 to 343) did not form complexes. We suggest that the ability of the mutant p53 phenotype to complex with wild type during cotranslation may contribute to the transforming function of activated mutants of p53 in vivo.
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41
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Affiliation(s)
- V Rotter
- Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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42
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Meek DW, Eckhart W. Mutation of the serine 312 phosphorylation site does not alter the ability of mouse p53 to inhibit simian virus 40 DNA replication in vivo. J Virol 1990; 64:1734-44. [PMID: 2157055 PMCID: PMC249311 DOI: 10.1128/jvi.64.4.1734-1744.1990] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Two mutations were introduced into the wild-type mouse p53 gene by oligonucleotide-directed mutagenesis. These mutations substituted alanine or aspartic acid for serine at position 312, which is constitutively phosphorylated. Phosphopeptide mapping of the mutant proteins, expressed in COS cells, confirmed the loss of phosphorylation at position 312. There were no changes in the ability of the mutant p53s to express the conformation-dependent epitope for monoclonal antibody PAb246 or to participate in complexes with the simian virus 40 (SV40) large T antigen. Replication of a plasmid containing the SV40 origin of replication was inhibited in COS cells by wild-type p53 and both of the phosphorylation site mutants with equal efficiency. A transforming mutant of p53, encoding valine at position 135, did not inhibit SV40 DNA replication in COS cells.
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Affiliation(s)
- D W Meek
- Molecular Biology and Virology Laboratory, Salk Institute for Biological Studies, San Diego, California 92138
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43
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Abstract
A tumour suppressor function for p53 is indicated in human lung cancer and in carcinoma of the colorectum. Loss of suppressor function, by mutation of the p53 gene, is associated with activation of p53 as an oncogene. The suppressor (wild type) and oncogenic (mutant) forms of the murine p53 protein are distinguishable at the molecular level by reactivity with anti-p53 monoclonal antibodies. For example, activated mutant p53 fails to react with PAb246 (p53-246 degrees). We now demonstrate that wild type p53 mRNA can be expressed either as p53-246+ or p53-246 degrees. We propose that p53-246 degrees may represent an allosteric variant of wild type p53 compatible with positive growth control. Thus, for wild type p53 the variants p53-246+ and p53-246 degrees may reflect suppressor and activator functions of p53 in the normal control of cell proliferation. For human p53 we present evidence that the epitope recognised by PAb1620 is analogous to that for PAb246 on murine p53. Thus the epitope for PAb1620 may prove to be of use as a marker for wild type human p53 with anti-oncogenic function.
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Affiliation(s)
- A Cook
- Department of Pathology, University of Cambridge, UK
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Stull SJ, Kyriakos M, Sharp GC, Bickel JT, Braley-Mullen H. Effects of anti-I-A and anti-I-E monoclonal antibodies on the induction and expression of experimental autoimmune thyroiditis in mice. Autoimmunity 1990; 6:23-36. [PMID: 1966583 DOI: 10.3109/08916939008993367] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Susceptibility to experimental autoimmune thyroiditis (EAT) in mice is linked to the I-A subregion of the major histocompatibility complex (MHC). The present study was undertaken to assess the effectiveness of anti-I-Ak monoclonal antibody (MAb) 10-2.16 in preventing or arresting the development of EAT. Spleen cells from CBA/J or (CBA/J x Balb/c) F1 mice given 10-2.16 prior to sensitization with mouse thyroglobulin (MTg) and adjuvant could not transfer EAT to normal recipients, and cells from these mice did not proliferate in vitro to MTg. Donor CBA/J mice given 10-2.16 before immunization and recipients of cells from such mice produced little MTg-specific IgG1 or IgG2b antibody but did produce nearly as much IgG2a as controls. The effects of in vivo treatment with 10-2.16 appear to be due to elimination of Ia + cells rather than to modulation of Ia or induction of suppressor T cells. When 10-2.16 was added to in vitro cultures it also prevented the proliferation and activation of sensitized CBA/J or F1 effector cell precursors. Other mAb specific for MHC class II gene products, but not associated with disease susceptibility, expressed by CBA/J (I-Ek) or F1 (I-Ad) mice (14-4-4S or MK-D6 respectively), also prevented in vivo sensitization, but did not block in vitro activation. Anti-I-Ak was also effective in preventing EAT if multiple injections of mAb were given to recipients of sensitized EAT effector cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- S J Stull
- Department of Microbiology, University of Missouri, Columbia 65212
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Mass MJ. Northern analyses of oncogene expression in rat tracheal epithelial (RTE) cell lines. Mol Carcinog 1990; 3:1-2. [PMID: 2157455 DOI: 10.1002/mc.2940030102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 1989. [PMID: 2476668 DOI: 10.1128/mcb.9.9.3982] [Citation(s) in RCA: 233] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We have investigated the role of the p53 gene in oncogenesis in vivo by generating transgenic mice carrying murine p53 genomic fragments isolated from a mouse Friend erythroleukemia cell line or BALB/c mouse liver DNA. Elevated levels of p53 mRNA were detected in several tissues of two transgenic lines tested. Increased levels of p53 protein were also detected in most of the tissues analyzed by Western blotting (immunoblotting). Because both transgenes encoded p53 proteins that were antigenically distinct from wild-type p53, it was possible to demonstrate that overexpression of the p53 protein was mostly, if not entirely, due to the expression of the transgenes. Neoplasms developed in 20% of the transgenic mice, with a high incidence of lung adenocarcinomas, osteosarcomas, and lymphomas. Tissues such as ovaries that expressed the transgene at high levels were not at higher risk of malignant transformation than tissues expressing p53 protein at much lower levels. The long latent period and low penetrance suggest that overexpression of p53 alone is not sufficient to induce malignancies and that additional events are required. These observations provide direct evidence that mutant alleles of the p53 oncogene have oncogenic potential in vivo and that different cell types show intrinsic differences in susceptibility to malignant transformation by p53. Since recent data suggest that p53 may be a recessive oncogene, it is possible that the elevated tumor incidence results from functional inactivation of endogenous p53 by overexpression of the mutant transgene. The high incidence of lung and bone tumors suggests that p53 transgenic mice may provide a useful model to investigate the molecular events that underlie these malignancies in humans.
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Lavigueur A, Maltby V, Mock D, Rossant J, Pawson T, Bernstein A. High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 1989; 9:3982-91. [PMID: 2476668 PMCID: PMC362460 DOI: 10.1128/mcb.9.9.3982-3991.1989] [Citation(s) in RCA: 90] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
We have investigated the role of the p53 gene in oncogenesis in vivo by generating transgenic mice carrying murine p53 genomic fragments isolated from a mouse Friend erythroleukemia cell line or BALB/c mouse liver DNA. Elevated levels of p53 mRNA were detected in several tissues of two transgenic lines tested. Increased levels of p53 protein were also detected in most of the tissues analyzed by Western blotting (immunoblotting). Because both transgenes encoded p53 proteins that were antigenically distinct from wild-type p53, it was possible to demonstrate that overexpression of the p53 protein was mostly, if not entirely, due to the expression of the transgenes. Neoplasms developed in 20% of the transgenic mice, with a high incidence of lung adenocarcinomas, osteosarcomas, and lymphomas. Tissues such as ovaries that expressed the transgene at high levels were not at higher risk of malignant transformation than tissues expressing p53 protein at much lower levels. The long latent period and low penetrance suggest that overexpression of p53 alone is not sufficient to induce malignancies and that additional events are required. These observations provide direct evidence that mutant alleles of the p53 oncogene have oncogenic potential in vivo and that different cell types show intrinsic differences in susceptibility to malignant transformation by p53. Since recent data suggest that p53 may be a recessive oncogene, it is possible that the elevated tumor incidence results from functional inactivation of endogenous p53 by overexpression of the mutant transgene. The high incidence of lung and bone tumors suggests that p53 transgenic mice may provide a useful model to investigate the molecular events that underlie these malignancies in humans.
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Affiliation(s)
- A Lavigueur
- Division of Molecular and Developmental Biology, Mount Sinai Hospital Research Institute, Toronto, Ontario, Canada
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Soussi T, Caron de Fromentel C, Stürzbecher HW, Ullrich S, Jenkins J, May P. Evolutionary conservation of the biochemical properties of p53: specific interaction of Xenopus laevis p53 with simian virus 40 large T antigen and mammalian heat shock proteins 70. J Virol 1989; 63:3894-901. [PMID: 2668561 PMCID: PMC250985 DOI: 10.1128/jvi.63.9.3894-3901.1989] [Citation(s) in RCA: 31] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
We have investigated the biochemical properties of Xenopus laevis p53. With an in vitro binding assay, we can detect a specific association between X. laevis p53 and simian virus 40 large T antigen. Furthermore, X. laevis p53 expressed in monkey COS cells is stably associated with this viral antigen. Like mammalian p53, X. laevis p53 in complex with simian virus 40 large T antigen exhibits a 20-fold increase of its half-life. On the other hand, X. laevis p53 is unable to associate either in vivo or in vitro with adenovirus type 5 E1B 55-kilodalton protein. We show by an immunological technique that X. laevis p53 forms specific complexes with mammalian hsp72 and hsp73 heat shock proteins only at a temperature well above the optimal growth temperature for X. laevis. Our results suggest that the protein-binding properties of p53 are closely related to the functional activity of the protein.
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Affiliation(s)
- T Soussi
- Unité d'Oncologie Moléculaire, Institut de Recherches Scientifiques sur le Cancer, Villejuif, France
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Abstract
Transcriptional deregulation of the p53 gene may play an important part in the genesis of some tumors. We report here an accurate determination of the transcriptional start sites of the human p53 gene and show that the majority of p53 mRNA molecules do not contain a postulated stem-loop structure at their 5' ends. Recombinant plasmids of the human p53 promoter-leader region fused to the bacterial chloramphenicol acetyltransferase gene (cat) were constructed. After transfection into rodent or human cells, a 350-base-pair fragment spanning the promoter region conferred 4% of the CAT activity mediated by the simian virus 40 early promoter/enhancer. We monitored the efficiency with which 15 3' and 5' promoter deletion constructs initiated transcription. Our results show that an 85-base-pair fragment, previously thought to have resided in exon 1, is all that is required for full promoter activity.
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Abstract
DNA clones of the wild-type p53 proto-oncogene inhibit the ability of E1A plus ras or mutant p53 plus ras-activated oncogenes to transform primary rat embryo fibroblasts. The rare clones of transformed foci that result from E1A plus ras plus wild-type p53 triple transfections all contain the p53 DNA in their genome, but the great majority fail to express the p53 protein. The three cell lines derived from such foci that express p53 all produce mutant p53 proteins with properties similar or identical to transformation-activated p53 proteins. The p53 mutants selected in this fashion (transformation in vitro) resemble the p53 mutants selected in tumors (in vivo). These results suggest that the p53 proto-oncogene can act negatively to block transformation.
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Affiliation(s)
- C A Finlay
- Princeton University, Department of Biology, New Jersey 08540-1014
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