c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage

Activation of the initiator caspase- 9 is essential for induction of apoptosis by developmental signals, oncogenic transformation, and genotoxic stress. The c- Abl tyrosine kinase is also involved in the apoptotic response to DNA damage. The present results demonstrate that c- Abl binds directly to caspase- 9. We show that cAbl phosphorylates caspase- 9 on Tyr- 153 in vitro and in cells treated with DNA damaging agents. Moreover, inhibition of c- Abl with STI571 blocked DNA damage- induced autoprocessing of caspase- 9 to the p35 subunit and activation of caspase- 3. Caspase- 9( Y153F) also attenuated DNA damage- induced processing of caspase- 9 to p35, activation of caspase- 3, and apoptosis. These findings indicate that caspase- 9 autoprocessing is regulated by c- Abl in the apoptotic response to genotoxic stress.