C-Abl-induced apoptosis, but not cell cycle arrest, requires mitogen-activated protein kinase kinase 6 activation

c-Abl is a ubiquitously expressed protein tyrosine kinase activated by DNA damage and implicated in two responses: cell cycle arrest and apoptosis. Th e downstream pathways by which c-Abl induces these responses remain unclear . We examined the effect of overexpression of c-Abl on the activation of mi togen-activated protein kinase pathways and found that overexpression of c- Abl selectively stimulated p38, while having no effect on c-Jun N-terminal kinase or on extracellular signal-regulated kinase. c-Abl-induced p38 activ ation was primarily mediated by mitogen-activated protein kinase kinase (MK K)6. A C-terminal truncation mutant of c-Abl showed no activity for stimula ting p38 and MKK6, while a kinase-deficient c-Abl mutant still retained a r esidual activity. We tested different forms of c-Abl for their ability to i nduce apoptosis and found that apoptosis induction correlated with the acti vation of the MKK6-p38 kinase pathway. Importantly, dominant-negative MKK6, but not dominant-negative MKK3 or p38, blocked c-Abl-induced apoptosis, Be cause overexpression of p38 blocks cell cycle G(1)/S transition, we also te sted whether the MKK6-p38 pathway is required for c-Abl-induced cell cycle arrest, and we found that neither MKK6 nor p38 dominant-negative mutants co uld relieve c-Abl-induced cell cycle arrest. Finally, DNA damage-induced MK K6 and p38 activation was diminished in c-Abl null fibroblasts. Our study s uggests that c-Abl is required for DNA damage-induced MKK6 and p38 activati on, and that activation of MKK6 by c-Abl is required for c-Abl-induced apop tosis but not c-Abl-induced cell cycle arrest.