Do Mutations Turn p53 into an Oncogene?

Abstract

The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis.

Keywords: TP53; gain of function; mutant TP53; oncogenic.

Figure 1

Analysis of TP53 genetic alterations. using cBioPortal data. (A). Frequency and type of TP53 alterations in different cancer types. Alterations in corresponding color codes are as follows: mutations (green), fusions (purple), amplifications (red), deep deletions (blue), and multiple alterations (grey). Source The cBio Cancer Genomics Portal is an open platform for exploring multidimensional cancer genomics data (cbioportal.org). (B) Distribution and frequency of different types of mutations along the p53 protein. Mutation types and corresponding color codes are as follows: missense mutations (green), truncating mutations (black), inframe mutations (red), and other mutations (Pink).

Figure 2

Mutant p53 gain of function (GOF) in metabolism and invasion. (A). Mutant p53 proteins promote invasion and migration by inhibiting p63 and p73 function, enhancing STAT3 (Signal Transducer And Activator Of Transcription) signaling and vascular endothelial growth factor receptor (VEGFR) expression. (B). Mutant p53 proteins promote glycolysis by upregulating glucose transporter GLUT1 translocation to the plasma membrane. In addition, mutant p53 proteins stimulate the mevalonate pathway through a physical interaction with SREBPs (Sterol Regulatory Element Binding Transcription Factors), and enhance lipogenesis by inhibiting AMP-activated protein kinase (AMPK) signaling.

Figure 3

Mutant p53 GOF and hypoxia. In response to hypoxia, p53 mutant forms a complex with hypoxia-inducible factor 1 (HIF-1) that physically binds the SWI/SNF chromatin remodeling complex, promoting expression of extracellular matrix (ECM) components such as Laminin-γ2 and type VIIa1 collagen (COL7A1). On the other hand, increased ECM stiffening induces HDAC6/ Heat shock protein 90 (Hsp90)-dependent stabilization of mutant p53 from ubiquitin-mediated proteolysis, through a mechanism that involves RhoA geranylgeranylation downstream of the mevalonate pathway. The purple and green arrows indicate promotion and inhibition, respectively.