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 c-Abl 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.
Raina
Deepak
D
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Pandey
Pramod
P
Ahmad
Rehan
R
Bharti
Ajit
A
Ren
Jian
J
Kharbanda
Surender
S
Weichselbaum
Ralph
R
Kufe
Donald
D
D017209:Apoptosis; D001549:Benzamides; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D000068877:Imatinib Mesylate; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D020298:U937 Cells
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases