p53 mediates Bcl-2 phosphorylation and apoptosis via activation of the Cdc42/JNK1 pathway

Citation
A. Thomas et al., p53 mediates Bcl-2 phosphorylation and apoptosis via activation of the Cdc42/JNK1 pathway, ONCOGENE, 19(46), 2000, pp. 5259-5269
Citations number
67
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ONCOGENE
ISSN journal
0950-9232 → ACNP
Volume
19
Issue
46
Year of publication
2000
Pages
5259 - 5269
Database
ISI
SICI code
0950-9232(20001102)19:46<5259:PMBPAA>2.0.ZU;2-K
Abstract
A member of the small G protein family, cdc42, was isolated from a screen u ndertaken to identify p53-inducible genes during apoptosis in primary baby rat kidney (BRK) cells transformed with E1A and a temperature-sensitive mut ant p53 using a PCR-based subtractive hybridization method. Cdc42 is a GTPa se that belongs to the Rho/Rac subfamily of Ras-like GTPases, In response t o external stimuli, Cdc42 is known to transduce signals to regulate the org anization of the actin cytoskeleton, induce DNA synthesis in quiescent fibr oblasts, and promote apoptosis in neuronal and immune cells. In this study, we have demonstrated that cdc42 mRNA and protein were up-regulated in the presence of wild-type p53 in BRK cells, followed by cytoplasmic to plasma m embrane translocation of Cdc42, Overexpression of Cdc42 in the presence of a dominant-negative mutant p53 induced apoptosis rapidly, indicating that C dc42 functions downstream of p53, Furthermore, stable expression of a domin ant-negative mutant of Cdc42 partially inhibited p53-mediated apoptosis, Th e Bcl-2 family members Bcl-x(L), and the adenovirus protein E1B 19K, inhibi ted Cdc42-mediated apoptosis, whereas Bcl-2 did not. We provide evidence th at PAK1 and JNK1 may play a role downstream of Cdc42 to transduce its apopt otic signal. Cdc42/PAK1 activates JNK1-induced phosphorylation of Bcl-2, th ereby inactivating its function, and that a phosphorylation resistant mutan t (Bcl-2S70,87A,T56,74A) gains the ability to inhibit Cdc42- and p53-mediat ed apoptosis, Thus, one mechanism by which p53 promotes apoptosis is throug h activation of Cdc42 and inactivation of Bcl-2.