Mutant p53: Multiple Mechanisms Define Biologic Activity in Cancer

Abstract

The functional importance of p53 as a tumor suppressor gene is evident through its pervasiveness in cancer biology. The p53 gene is the most commonly altered gene in human cancer; however, not all genetic alterations are biologically equivalent. The majority of alterations involve p53 missense mutations that result in the production of mutant p53 proteins. Such mutant p53 proteins lack normal p53 function and may concomitantly gain novel functions, often with deleterious effects. Here, we review characterized mechanisms of mutant p53 gain of function in various model systems. In addition, we review mutant p53 addiction as emerging evidence suggests that tumors may depend on sustained mutant p53 activity for continued growth. We also discuss the role of p53 in stromal elements and their contribution to tumor initiation and progression. Lastly, current genetic mouse models of mutant p53 in various organ systems are reviewed and their limitations discussed.

Keywords: TP53; cancer; gain of function; mouse models of cancer; mutant proteins; p53 mutation; stroma.

Figure 1

(A) Mutant p53 interacts with transcription factors not normally bound by wildtype p53, such as p63, p73, and Smad. The activity of downstream targets is disrupted, resulting in GOF properties. (B) Mutant p53 complexes with transcription factors, such as Ets2 and SREBP, not typically bound by wildtype p53. The results are aberrant activation of genes and downstream effectors that promote GOF properties.