The p53 tumor suppressor: a master regulator of diverse cellular processes and therapeutic target in cancer

Abstract

The tumor suppressor p53 has been implicated in a growing number of biological processes, including cell cycle arrest, senescence, apoptosis, autophagy, metabolism, and aging. Activation of p53 in response to oncogenic stress eliminates nascent tumor cells by apoptosis or senescence. p53 is regulated at the protein level by posttranslational modifications such as phosphorylation and acetylation. A p53 antisense gene, Wrap53, enhances p53 mRNA levels via the 5'UTR. Lack of Wrap53 transcripts that overlap with p53 abrogates the p53 DNA damage response. Around half of all human tumors carry p53 mutation that disrupt p53 specific DNA binding, and transcriptional transactivation of target genes. Reactivation of mutant p53 is a promising strategy for novel cancer therapy. The small molecule PRIMA-1 restores wild type conformation and DNA binding to mutant p53, induces mutant p53-dependent apoptosis, and inhibits tumor growth in vivo. The PRIMA-1 analog APR-246 is currently tested in a phase I clinical trial. Improved understanding of the p53 pathway should lead to better diagnosis and treatment of cancer in the future.