Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy

Tumor suppressor p53 plays a central role in tumor suppression. p53 is the most frequently mutated gene in human cancer, and over half of human cancers contain p53 mutations. Majority of p53 mutations in cancer are missense mutations, leading to the expression of full-length mutant p53 (mutp53) protein. While the critical role of wild-type p53 in tumor suppression has been firmly established, mounting evidence has demonstrated that many tumor-associated mutp53 proteins not only lose the tumor-suppressive function of wild-type p53 but also gain new activities to promote tumorigenesis independently of wild-type p53, termed gain-of-function. Mutant p53 protein often accumulates to very high levels in tumors, contributing to malignant progression. Recently, mutp53 has become an attractive target for cancer therapy. Further understanding of the mechanisms underlying mutp53 protein accumulation and gain-of-function will accelerate the development of targeted therapies for human cancer harboring mutp53. In this review, we summarize the recent advances in the studies on mutp53 protein accumulation and gain-of-function and targeted therapies for mutp53 in human cancer. [Display omitted] •p53 is the most commonly mutated gene in human cancer.•Mutant p53 is frequently accumulated to high levels in cancer.•Mutant p53 often displays gain-of-function oncogenic activities.•Targeting mutp53 is a promising therapeutic strategy for cancer.