Mechanisms of p53-dependent apoptosis

Cellular stresses, such as growth factor deprivation, DNA damage or oncogen e expression, lead to stabilization and activation of the p53 turnout suppr essor protein. Depending on the cellular context, this results in one of tw o different outcomes: cell cycle arrest or apoptotic cell death. Cell death induced through the p53 pathway is executed by the caspase proteinases, wh ich, by cleaving their substrates, lead to the characteristic apoptotic phe notype. Caspase activation by p53 occurs through the release of apoptogenic factors from the mitochondria, including cytochrome c and Smac/DIABLO. Rel eased cytochrome c allows the formation of a high-molecular weight complex, the apoptosome, which consists of the adapter protein Apaf-1 and caspase 9 , which is activated following recruitment into the apoptosome. Active casp ase 9 then cleaves and activates the effector caspases, such as caspases-3 and -7, which execute the death program. Released Smac/DIABLO facilitates c aspase activation through repression of the IAP caspase inhibitor proteins. The release of mitochondrial apoptogenic factors is regulated by the pro- and anti-apoptotic Bcl-2 family proteins, which either induce or prevent th e permeabilization of the outer mitochondrial membrane, The mechanism by wh ich p53 signals to the Bcl-2 family proteins is unclear. It was shown that some of the pro-apoptotic family members, such as Bax, Noxa or PUMA, are tr anscriptional targets of p53. In addition, transcription-independent, pro-a poptotic activities of p53 have been described. The elucidation of the p53- dependent pathway, resulting in mitochondrial outer membrane permeabilizati on through the pro-apoptotic Bcl-2 family proteins, is a key to unveiling t he mechanism of stress-induced apoptosis.