Regulation of p53 Activity and Associated Checkpoint Controls

Abstract

Cancer develops when numerous genetic changes accumulate in pathways that regulate cell proliferation, differentiation, and apoptosis. In eukaryotes, failure to control cell division and loss of genomic stability are the hallmarks of neoplastic cells. Eukaryotic cells have evolved intricate signaling pathways, called checkpoints that can both halt uncontrolled proliferation and delay cell cycle progression in response to genotoxic stress, oncogenic activation, and aberrant proliferative signals. The p53 tumor suppressor encodes one such checkpoint protein. Although various mechanisms activate numerous positive and negative regulators required for cell cycle signaling cascades, these proteins relay their signals through many of the same essential components. Given the importance of these proteins in regulating cell cycle progression, many are altered during tumorigenesis. Herein, we provide an overview of the signaling mechanisms that control cell cycle progression and a primer of some of the most clinically promising agents targeting p53 and associated pathways that impact the cell cycle.