Nuclear and mitochondrial apoptotic pathways of p53

In contrast to p53-mediated cell cycle arrest, the mechanisms of p53-mediat ed apoptosis in response to cellular stresses such as DNA damage, hypoxia a nd oncogenic signals still remain poorly understood. Elucidating these path ways is all the more pressing since there is good evidence that the activat ion of apoptosis rather than cell cycle arrest is crucial in p53 tumor supp ression. Moreover, the therapeutic interest in p53 as the molecular target of anticancer intervention rests mainly on its powerful apoptotic capabilit y. This puzzling elusiveness suggests that p53 not only engages a plethora of downstream pathways but itself might possess a biochemical flexibility t hat goes beyond its role as a mere transcription factor. Recent evidence of a direct pro-apoptotic role of p53 protein at mitochondria suggests a syne rgistic effect with its transcriptional activation function and brings an u nexpected new level of complexity into p53 apoptotic pathways. (C) 2001 Pub lished by Elsevier Science B.V. on behalf of the Federation of European Bio chemical Societies.