p53 and cellular stress–induced apoptosis.
Various stress stimuli activate the p53 protein, which promotes cell-cycle arrest to enable DNA repair or apoptosis to eliminate defective cells. A key player in the regulation of p53 is Mdm2, which binds to p53 and inhibits the DNA binding activity as well as the transcription rate of the p53 gene. In a negative feedback loop, p53 binds to the mdm2 gene and stimulates its transcription. Another inhibitor is the Rb protein, which prevents the apoptotic function of p53. p53 induces various target genes, such as the cell-cycle regulators p21Waf1, GADD45, and cyclin G. Proapoptotic p53 target proteins include Bax, CD95, DR5, IGF-BP3, NOXA, p53AIP1, and (in Drosophila) Rpr. ROS production may be mediated by the p53-inducible gene PIG3 and may contribute to cytochrome c release from mitochondria. Taken together, the apoptotic target genes of p53 may need to act in concert by activating parallel apoptotic pathways to mount a full apoptotic response.
