INVOLVEMENT OF P85 IN P53-DEPENDENT APOPTOTIC RESPONSE TO OXIDATIVE STRESS

Reactive oxygen species have damaging effects on cellular components a nd so trigger defensive responses by the cell(1,2) and even programmed cell death(3,4), although the mechanisms by which mammalian cells tra nsmit signals in response to oxidative damage are unknown. We report h ere that the protein p85, a regulator of the signalling protein phosph atidyl-3-OH kinase (PI(3)K), participates in the cell death process th at is induced in response to oxidative stress and that this role of p8 5 in apoptosis does not involve PI(S)K. We show that disruption of p85 by homologous recombination impairs the cellular apoptotic response t o oxidative stress. Because the protein p53 is required for cell death induced by oxidative damage, we examined the relation between p85 and p53. Using a chimaeric p53 fusion protein with the oestrogen receptor (p53ER) to supply p53 (p53 is induced upon binding of p53ER to oestra diol) in a p53-deficient cell line, we found that p85 is upregulated b y p53 and that its involvement in p53-mediated apoptosis is independen t of PI(3)K. We propose that p85 acts as a signal transducer in the ce llular response to oxidative stress, mediating cell death regulated by p53.