Gain-of-Function Mutations in p53 in Cancer Invasiveness and Metastasis

Abstract

Forty years of research has proven beyond any doubt that p53 is a key regulator of many aspects of cellular physiology. It is best known for its tumor suppressor function, but it is also a regulator of processes important for maintenance of homeostasis and stress response. Its activity is generally antiproliferative and when the cell is damaged beyond repair or intensely stressed the p53 protein contributes to apoptosis. Given its key role in preventing cancer it is no wonder that it is the most frequently mutated gene in human cancer. Surprisingly, a subset of missense mutations occurring in p53 (gain-of-function) cause it to lose its suppressor activity and acquire new functionalities that turn the tumor suppressor protein into an oncoprotein. A solid body of evidence exists demonstrating increased malignancy of cancers with mutated p53 in all aspects considered “hallmarks of cancer”. In this review, we summarize current findings concerning the cellular processes altered by gain-of-function mutations in p53 and their influence on cancer invasiveness and metastasis. We also present the variety of molecular mechanisms regulating these processes, including microRNA, direct transcriptional regulation, protein−protein interactions, and more.

Keywords

• cancer
• p53
• gain-of-function
• metastasis
• invasiveness
• review