High resolution

Module 4: Figure p53 function

The activation and function of p53.

The transcriptional activity of p53 is regulated by a complex set of processes that control its stability, activation and translocation. The transcriptional activity of p53 is normally kept at a low level either by its binding to various proteins such as p53-associated parkin-like cytoplasmic protein (PARC), which effectively acts as a buffer, or by its rapid turnover. The ubiquitin ligase mouse double minute-2 (MDM2) is responsible for the degradation and for the nuclear export of p53. The activity of MDM2 is inhibited by alternative reading frame (ARF), which acts to stabilize p53. A variety of stressful stimuli such as DNA damage and ionizing radiation stimulate the protein kinases and acetylases responsible for the post-translational modifications (Module 4: Figure p53 domains) that activate p53. Once activated, it accumulates in the nucleus where it binds to the p53-responsive element found on a large number of genes, many of which function to control cell cycle arrest or apoptosis. One of the genes switched on by p53 codes for MDM2, thus setting up a negative-feedback loop to curb the activity of p53.