The inherent instability of mutant p53 is alleviated by Mdm2 or p16^INK4a loss

Abstract

The p53 tumor suppressor is often disrupted in human cancers by the acquisition of missense mutations. We generated mice with a missense mutation at codon 172 that mimics the p53R175H hot spot mutation in human cancer. p53 homozygous mutant mice have unstable mutant p53 in normal cells and stabilize mutant p53 in some but not all tumors. To investigate the significance of these data, we examined the regulation of mutant p53 stability by Mdm2, an E3 ubiquitin ligase that targets p53 for degradation, and p16 INK4a, a member of the Rb tumor suppressor pathway. Mice lacking Mdm2 or p16INK4a stabilized mutant p53, and revealed an earlier age of tumor onset than p53 mutant mice and a gain-of-function metastatic phenotype. Analysis of tumors from p53 homozygous mutant mice with stable p53 revealed defects in the Rb pathway. Additionally, ionizing radiation stabilizes wild-type and mutant p53. Thus, the stabilization of mutant p53 is not a given but it is a prerequisite for its gain-of-function phenotype. Since mutant p53 stability mimics that of wild-type p53, these data indicate that drugs aimed at activating wild-type p53 will also stabilize mutant p53 with dire consequences.[Keywords: Metastasis; mouse models; gain of function; p53 stability] Supplemental material is available at http://www.genesdev.org.

Mdm2-mediated ubiquitylation: p53 and beyond

“…Knock-in mice expressing p53R175H, a mutant form of p53 frequently found in human cancers, have recently been generated and have provided in vivo evidence for the importance of the Mdm2-mutant p53 interaction. 106 Cells from mice homozygous for the p53R172H mutation have normal levels of mutant p53. In the absence of Mdm2, however, p53R172H becomes stable in normal cells and leads to its gain-of-function activities in vivo.…”

“…The tissue-specific nature of mutant p53 stabilization indicates that either p53 is not important in some cell types or that other negative regulators of p53 take precedence over Mdm2 in specific cell types. 106 However, as p53 can no longer activate transcription of the Mdm2, the negative feedback loop cannot be established; hence, upon DNA damage, mutant p53 is stabilized. 106 In heterozygous mice with one mutant and one wild-type p53 allele, the increased stability of mutant p53 in response to DNA damage functions as a dominant negative and dampens wild-type p53 activity.…”

“…106 However, as p53 can no longer activate transcription of the Mdm2, the negative feedback loop cannot be established; hence, upon DNA damage, mutant p53 is stabilized. 106 In heterozygous mice with one mutant and one wild-type p53 allele, the increased stability of mutant p53 in response to DNA damage functions as a dominant negative and dampens wild-type p53 activity. Proliferating cells with mutant p53 that receive DNA damage signals therefore do not need to lose the wild-type p53 allele to accumulate additional alterations during tumor development.…”

“…The loss of Mdm2, which mimics the inhibition of the Mdm2-p53 interaction, led to a stabilization of mutant p53 and an increased incidence of metastasis as compared with mice lacking p53. 106 The model predicts that patients with mutations in p53 will stabilize mutant p53 upon treatment with small molecule inhibitors of Mdm2, regardless of the length of small molecule administration. In tumors with p53 loss of heterozygousity, the stabilization of mutant p53 is likely to yield a worse outcome.…”

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

“…The failure of mutant p53 to induce its antagonist Mdm2 contributes to this stabilization, as Mdm2 normally promotes p53 degradation through its ubiquitin ligase activity. However, the mutation of p53 alone does not always result in p53 accumulation (Terzian et al, 2008). Thus, additional mechanisms, on top of missing Mdm2 induction, lead to the high levels of mutant p53 in tumors.…”