A MODEL FOR P53-INDUCED APOPTOSIS

The inactivation of the p53 gene in a large proportion of human cancer s has inspired an intense search for the encoded protein's physiologic al and biological properties. Expression of p53 induces either a stabl e growth arrest or programmed cell death (apoptosis). In human colorec tal cancers, the growth arrest is dependent on the transcriptional ind uction of the protein p21(WAF1/CIP1) (ref. 1), but the mechanisms unde rlying the development of p53-dependent apoptosis are largely unknown( 2). As the most well documented biochemical property of p53 is its abi lity to activate transcription of genes, we examined in detail the tra nscripts induced by p53 expression before the onset of apoptosis. Of 7 ,202 transcripts identified, only 14 (0.19%) were found to be markedly increased in p53-expressing cells compared with control cells. Striki ngly, many of these genes were predicted to encode proteins that could generate or respond to oxidative stress, including one that is implic ated in apoptosis in plant meristems, These observations stimulated ad ditional biochemical and pharmacological experiments suggesting that p 53 results in apoptosis through a three-step process: (1) the transcri ptional induction of redox-related genes; (2) the formation of reactiv e oxygen species; and (3) the oxidative degradation of mitochondrial c omponents, culminating in cell death.