p53-mediated apoptosis: mechanisms and regulation.

Abstract

The p53 tumor suppressor gene is a key target for inactivation in human cancer. One of the main biological functions of the p53 protein is the positive regulation of apoptosis in response to signals such as genomic damage and the aberrant activation of certain oncogenes. A transient transfection assay was utilized in order to study the mechanism and regulation of p53-mediated apoptosis in human cancer cells. It was found that the sequence specific transcriptional activation (SST) function of p53 is essential for apoptosis in certain cell types, but not in others. This implies the existence of at least two distinct mechanisms for p53-mediated apoptosis, one requiring the activation of specific target genes, and the other being SST-independent. Typically, both mechanisms may be triggered simultaneously, and their cooperation may be required for maximal apoptotic effects. In addition, in cells lacking the function of the Rb tumor suppressor, the apoptotic activity of p53 could be inhibited by reconstitution of active Rb. p53-mediated apoptosis could also be inhibited by the protein encoded by the mdm2 oncogene. The latter inhibition required the formation of complexes between the Mdm2 protein and p53, and operated only on SST-dependent apoptosis but not SST-independent apoptosis. Together, the data imply that p53 induces apoptosis through the activation of multiple biochemical pathways, and that the efficiency of the process is dictated by the cellular context.