Journal Article

When mutants gain new powers: news from the mutant p53 field

Brosh, Ran, Rotter, Varda

2009

Overview

Mutant p53 proteins not only lose their tumour suppressive ability, but also gain new properties that promote tumorigenesis. What are these properties and what are the clinical implications? Key Points The tumour suppressor p53 (encoded by TP53 in humans) functions primarily as a transcription factor, which, upon cellular stress signals, regulates a plethora of genes that promote cell cycle arrest, senescence, apoptosis, differentiation, DNA repair and other processes. TP53 is somatically mutated in the majority of sporadic human cancers, and mutations in TP53 are also associated with Li–Fraumeni Syndrome, a familial cancer predisposition syndrome. The majority of cancer-associated mutations in TP53 are missense mutations in its DNA-binding domain. These mutations usually lead to the formation of a full-length mutant protein (mutant p53) incapable of activating p53 target genes and suppressing tumorigenesis. Besides losing their wild-type activities, many p53 mutants also function as dominant-negative proteins that inactivate wild-type p53 expressed from the remaining wild-type allele. Moreover, some mutant p53 forms also acquire new oncogenic properties that are independent of wild-type p53, known as 'gain-of-function' properties. In the past three decades ample data were collected in support of the importance of mutant p53 gain-of-function properties for tumorigenesis. These data include cell culture studies that demonstrated the capability of mutant p53 to impinge on pivotal cellular regulatory networks, mouse models that established the ability of mutant p53 to increase tumour aggressiveness and metastatic potential, as well as clinical studies that revealed associations between TP53 mutations and poor clinical outcome in a variety of malignancies. This Review describes recent advances in the research field of mutant p53, with an emphasis on the transcriptional effects of mutant p53, the expression signatures associated with TP53 mutations in vitro and in vivo and the diagnostic, prognostic and predictive value of TP53 mutations in human cancer. Ample data indicate that mutant p53 proteins not only lose their tumour suppressive functions, but also gain new abilities that promote tumorigenesis. Moreover, recent studies have modified our view of mutant p53 proteins, portraying them not as inert mutants, but rather as regulated proteins that influence the cancer cell transcriptome and phenotype. This influence is clinically manifested as association of TP53 mutations with poor prognosis and drug resistance in a growing array of malignancies. Here, we review recent studies on mutant p53 regulation, gain-of-function mechanisms, transcriptional effects and prognostic association, with a focus on the clinical implications of these findings.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Cancer cells / Cancer Research / Carcinogenesis / Control / Disease Models, Animal / Gene mutations / Genes, p53 - genetics / Genetic aspects / Health aspects / Humans / Mice / Mutation / Neoplasms - metabolism / Prognosis / review-article / Risk factors / Single nucleotide polymorphisms / Transcription, Genetic - genetics / Tumor Suppressor Protein p53 - genetics