Why is p53 protein stabilized in neoplasia? Some answers but many more questions?

The Journal of Pathology
V SaveP A Hall

Abstract

The p53 pathway provides a physiological system for integrating signals from diverse insults and eliciting adaptive cellular responses that include (but importantly are not restricted to) growth arrest and apoptosis. Defects in the pathway are prevalent in cancer, most notably being associated with mis-sense mutations in p53 itself. This leads to the inability of p53 to act as a transcription factor and thus to the non-occurrence of downstream events. Recent data indicate that the stability (and hence level) of p53 protein in cells is regulated by its interaction with mdm2: this results in enhanced p53 degradation by ubiquitin-mediated events. Since mdm2 is itself regulated by p53, loss of function of p53 leads to lack of mdm2 and thus to p53 protein accumulation. This provides a mechanistic explanation for the observation that p53 accumulation is associated with neoplasia. It may be that accumulation of p53 in the absence of p53 mutation can occur as a consequence of mdm2 defects, as well as being a physiological response in many situations. Another recent development is the recognition of p53 homologues (p73 alpha, p73 beta, and KET) which have many sequence and probable structural features in common with p53. It seems likely...Continue Reading

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Apr 20, 2001·The New England Journal of Medicine·T WatanabeS R Hamilton
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