Regulation of DNA damage-induced apoptosis by the c-Abl tyrosine kinase.
Activation of the c-Abl protein tyrosine kinase by certain DNA-damaging agents contributes to downregulation of Cdk2 and G1 arrest by a p53-dependent mechanism. The present work investigates the potential role of c-Abl in apoptosis induced by DNA damage. Transient transfection studies with wild-type, but not kinase-inactive, c-Abl demonstrate induction of apoptosis. Cells that stably express inactive c-Abl exhibit resistance to ionizing radiation-induced loss of clonogenic survival and apoptosis. Cells null for c-abl are also impaired in the apoptotic response to ionizing radiation. We further show that cells deficient in p53 undergo apoptosis in response to expression of c-Abl and exhibit decreases in radiation-induced apoptosis when expressing inactive c-Abl. These findings suggest that c-Abl kinase regulates DNA damage-induced apoptosis.
Yuan
Z M
ZM
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Huang
Y
Y
Ishiko
T
T
Kharbanda
S
S
Weichselbaum
R
R
Kufe
D
D
D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl