p53 and stress in the ER

The ability of p53 to induce apoptosis and senescence clearly needs to be tightly regulated. Hyperactivation of p53 could compromise organism survival, if too many cells were driven to undergo apoptosis or permanent senescence, as illustrated by the premature aging phenotype of mice expressing a mut...

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Bibliographic Details
Published in:Genes & development 2004-02, Vol.18 (3), p.241-244
Main Authors: Stavridi, Elena S, Halazonetis, Thanos D
Format: Article
Language:English
Subjects:
Activating Transcription Factor 6
Animals
DNA-Binding Proteins
Endoplasmic Reticulum - metabolism
Gene Expression Regulation
Genes, p53
Glycogen Synthase Kinase 3 - metabolism
Glycogen Synthase Kinase 3 beta
Humans
Models, Biological
Mutation
Protein Folding
Stress, Physiological - genetics
Transcription Factors
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Summary:The ability of p53 to induce apoptosis and senescence clearly needs to be tightly regulated. Hyperactivation of p53 could compromise organism survival, if too many cells were driven to undergo apoptosis or permanent senescence, as illustrated by the premature aging phenotype of mice expressing a mutant p53 gene that leads to increased p53 activity. Accordingly, there are several mechanisms to control p53 activity. Functionally, one of the most important such mechanisms involves the ubiquitin ligase Mdm2, which participates with p53 in a negative feedback loop: p53 activates transcription of the mdm2 gene, whose protein product then targets p53 for ubiquitin-dependent degradation. Thus, any increase in p53 activity is accompanied by increased p53 degradation. This and other mechanisms to control p53 activity can, of course, be overcome by genotoxic stress. Genotoxic stress can activate p53 through several pathways that typically involve posttranslational modifications of the N or C terminus of p53. The ATM protein kinase, which is activated in response to DNA DSBs, is a key player in p53 activation. ATM activates the Chk2 kinase, which in turn phosphorylates p53 on Ser 20, leading to dissociation of p53 from Mdm2 and increased p53 protein levels. A similar pathway is thought to operate in response to replication blocks, although in this case, ATR, an ATM-related kinase, is activated, and p53 phosphorylation on Ser 20 is most likely mediated by both Chk2 and Chk1.
ISSN:0890-9369
DOI:10.1101/gad.1181704