Mutant p53 gain-of-function in cancer

Abstract

In its wild-type form, p53 is a major tumor suppressor whose function is critical for protection against cancer. Many human tumors carry missense mutations in the TP53 gene, encoding p53. Typically, the affected tumor cells accumulate excessive amounts of the mutant p53 protein. Various lines of evidence indicate that, in addition to abrogating the tumor suppressor functions of wild-type p53, the common types of cancer-associated p53 mutations also endow the mutant protein with new activities that can contribute actively to various stages of tumor progression and to increased resistance to anticancer treatments. Collectively, these activities are referred to as mutant p53 gain-of-function. This article addresses the biological manifestations of mutant p53 gain-of-function, the underlying molecular mechanisms, and their possible clinical implications.

Figure 1.

Mechanisms of transcriptional regulation by mutp53. Positive and negative effects on transcription are indicated by + and −, respectively. In (A), mutp53 binds to p63 and/or p73 protein isoforms, inhibiting their interaction with cognate binding sites on the DNA (p63/p73BS) and blocking the activation of p63/p73 target genes. In (B), mutp53 engages in protein–protein interactions with transcription factor X (TFX) and is tethered to the binding site of TFX on DNA; through its TAD, mutp53 recruits transcriptional coactivators (CoAct) such as p300 (Di Agostino et al. 2006), and augments transcription of TFX target genes. In (C), mutp53 is proposed to be tethered to DNA through transcription factor Y (TFY), but instead of recruiting transcriptional coactivators it recruits corepressors, as has been shown for wt p53 (Murphy et al. 1999); what dictates whether mutp53 will recruit coactivators or corepressors is presently unknown, but in both (B) and (C), mutp53 will be found on chromatin at the appropriate TF binding sites. In (D), mutp53 is shown to associate with specific DNA elements, such as matrix attachment regions (MAR) (Gohler et al. 2005); it is proposed that this may block the recruitment of TFY to an adjacent binding site, resulting in transcriptional inhibition. Additional mechanisms most likely also exist.