Induction of genetic instability by gain-of-function p53 cancer mutants.

p53 plays critical roles in tumor suppression and the loss of its function is required for cancer progression. In this context, the p53 gene is the most commonly mutated tumor suppressor gene in human cancers. The majority of the p53 gene mutations in human cancers are missense mutations, leading to the expression of the full-length mutant p53 protein in cancer cells. In addition to the loss of tumor suppression activity, p53 cancer mutants gain new oncogenic activities to promote tumorigenesis and drug resistance. Recent studies have identified a novel gain-of-function of p53 cancer mutants in inducing genetic instability by inactivating critical tumor suppressors such as ATM. Genetic instability is a common mechanism by which cancer cells efficiently accumulate genetic mutations to promote their growth, survival and metastatic potential. Therefore, this gain-of-function of p53 cancer mutants could play important roles in tumorigenesis and drug resistance of various types of human cancers. In addition, because many cancer therapies such as radiation therapy suppress or kill cancer cells by activating ATM-dependent responses to DNA double-stranded break damage, elucidation of this gain-of-function of p53 cancer mutants will have important implications on cancer therapy.