The Mdm network and its regulation of p53 activities: a rheostat of cancer risk

Abstract

The potent transcriptional activity of p53 (Trp53, TP53) must be kept in check for normal cell growth and survival. Tumors, which drastically deviate from these parameters, have evolved multiple mechanisms to inactivate TP53, the most prevalent of which is the emergence of TP53 missense mutations, some of which have gain-of-function activities. Another important mechanism by which tumors bypass TP53 functions is via increased levels of two TP53 inhibitors, MDM2, and MDM4. Studies in humans and in mice reveal the complexity of TP53 regulation and the exquisite sensitivity of this pathway to small changes in regulation. Here, we summarize the factors that impinge on TP53 activity and thus cell death/arrest or tumor development.

Keywords: Mdm2; Mdm4; TCGA; TP53; Trp53; mouse models; p53.

Figure 1. A model showing some of the effectors of the p53 pathway

Dotted lines denote tumor suppressors and solid lines denote activated or over produced proteins that contribute to tumor development. The shaded box denotes p53-independent functions of Mdm2. Mdm2 binds and inhibits Nbs1, a member of the MRN complex responsible for DNA break repair.

Figure 2. Amplification of MDM4 or MDM2 genes in specific cancers can result in decreased patient survival

Gene copy number alterations and survival data were obtained from the cBioPortal for Cancer Genomics (http://www.cbiopor2tal.org/public-portal/) July 2013 (Cerami, et al., 2012; Gao, et al., 2013). Kaplan-Meier survival curves of patients with (A) uterine carcinoma with and without MDM4 amplification and (B) glioblastoma with and without MDM2 amplification. The number (n) of samples of each is indicated, and p values were calculated by log-rank tests comparing survival between groups.

Figure 3. Small differences in p53 levels alter tumor development and survival

Survival curves of p53 mutant mice with various alleles. The p53neo allele is a hypomorphic allele that expresses approximately 7% of wild type p53 levels (Wang, et al., 2011). The percentages indicated equal the levels of p53 protein detected by western blot analysis compared to the wild type, which was set at 100%. From (Wang, et al., 2011) with permission.