title: c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage.
abstract: 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.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Raina
authors.forename: Pramod
authors.initials: P
authors.lastname: Pandey
authors.forename: Rehan
authors.initials: R
authors.lastname: Ahmad
authors.forename: Ajit
authors.initials: A
authors.lastname: Bharti
authors.forename: Jian
authors.initials: J
authors.lastname: Ren
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Ralph
authors.initials: R
authors.lastname: Weichselbaum
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: 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
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases