Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents.
The product of the c-abl gene is a non-receptor tyrosine kinase that is localized to the nucleus and cytoplasm. The precise function of c-Abl is unknown. Here we show that ionizing radiation activates c-Abl. Similar results were obtained with the alkylating agents cis-platinum and mitomycin C. We also demonstrate that cells deficient in c-Abl fail to activate Jun kinase (JNK/SAP kinase) after ionizing radiation or alkylating agent exposure and that reconstitution of c-Abl in these cells restores that response. In contrast, the stress response to tumour-necrosis factor is stimulated by a c-Abl-independent mechanism. These findings indicate that c-abl is involved in the stress response to DNA-damaging agents.
Kharbanda
S
S
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ren
R
R
Pandey
P
P
Shafman
T D
TD
Feller
S M
SM
Weichselbaum
R R
RR
Kufe
D W
DW
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D008937:Mitomycins / Q000494:pharmacology; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011839:Radiation, Ionizing
D008937:Mitomycins; D010455:Peptides; D016755:Proto-Oncogene Proteins c-jun; D004247:DNA; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D002945:Cisplatin