Abstract
Approximately 50% of sporadic human tumors harbor somatic mutations in the p53 gene locus, while germ line mutations confer a high familial risk and are associated with Li-Fraumeni Syndrome patients. The p53 tumor suppressor protein is often referred to as the “guardian of the genome” since its response to DNA-damage or checkpoint failure gives rise to a series of anti-proliferative responses. One of the most important functions of p53 is its ability to induce apoptosis, while disruption of this route can promote tumor progression and chemo resistance. Besides its ability to promote apoptosis through transcription dependent mechanisms, p53 may also be able to activate apoptosis independent of transcriptional regulation. Therefore, to ensure normal cell growth, p53 levels and activity are tightly regulated. Upon diverse forms of cellular stress the steady state levels and transcriptional activity of p53 are considerably increased. The stabilization and activation of p53 are a result of hindered inhibition by its negative regulators, e.g. Mdmx (also known as Mdm4) and Mdm2, while on the other hand activators such as HIPK2 and DYRK2 enhance the p53 response. The continually increasing understanding of the mechanisms of regulation of p53 may provide the basis for new drug designs that could eventually lead to therapeutics to reactivate p53 in cancers.
Keywords: p53, apoptosis, Mdm2, Mdmx, Bcl2-proteins, HIPK2, DYRK2, Nutlin3, RITA
Current Cancer Drug Targets
Title: p53: A Guide to Apoptosis
Volume: 8 Issue: 2
Author(s): Erik Meulmeester and Aart G. Jochemsen
Affiliation:
Keywords: p53, apoptosis, Mdm2, Mdmx, Bcl2-proteins, HIPK2, DYRK2, Nutlin3, RITA
Abstract: Approximately 50% of sporadic human tumors harbor somatic mutations in the p53 gene locus, while germ line mutations confer a high familial risk and are associated with Li-Fraumeni Syndrome patients. The p53 tumor suppressor protein is often referred to as the “guardian of the genome” since its response to DNA-damage or checkpoint failure gives rise to a series of anti-proliferative responses. One of the most important functions of p53 is its ability to induce apoptosis, while disruption of this route can promote tumor progression and chemo resistance. Besides its ability to promote apoptosis through transcription dependent mechanisms, p53 may also be able to activate apoptosis independent of transcriptional regulation. Therefore, to ensure normal cell growth, p53 levels and activity are tightly regulated. Upon diverse forms of cellular stress the steady state levels and transcriptional activity of p53 are considerably increased. The stabilization and activation of p53 are a result of hindered inhibition by its negative regulators, e.g. Mdmx (also known as Mdm4) and Mdm2, while on the other hand activators such as HIPK2 and DYRK2 enhance the p53 response. The continually increasing understanding of the mechanisms of regulation of p53 may provide the basis for new drug designs that could eventually lead to therapeutics to reactivate p53 in cancers.
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Cite this article as:
Meulmeester Erik and Jochemsen G. Aart, p53: A Guide to Apoptosis, Current Cancer Drug Targets 2008; 8 (2) . https://dx.doi.org/10.2174/156800908783769337
DOI https://dx.doi.org/10.2174/156800908783769337 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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