Activation of p38 mitogen-activated protein kinase by c-Abl-dependent and -independent mechanisms.
The p38 mitogen-activated protein (MAP) kinase defines a subgroup of the mammalian MAP kinases that are induced in response to lipopolysaccharide, hyperosmolarity, and interleukin 1. p38 MAP kinase appears to play a role in regulating inflammatory responses, including cytokine secretion and apoptosis. Here we show that diverse classes of DNA-damaging agents such as cisplatinum, 1-beta-D-arabinofuranosylcytosine, UV light, ionizing radiation, and methyl methanesulfonate activate p38 MAP kinase. We also demonstrate that cells deficient in c-Abl fail to activate p38 MAP kinase after treatment with cisplatinum and 1-beta-D-arabinofuranosylcytosine but not after exposure to UV and methyl methanesulfonate. Reconstitution of c-Abl in the Abl-/- cells restores that response. Similar results were obtained for induction of the Jun-NH2-kinase/stress-activated protein kinase. These findings indicate that p38 MAP and Jun-NH2-kinase/stress-activated protein kinases are differentially regulated in response to different classes of DNA-damaging agents.
Pandey
P
P
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Raingeaud
J
J
Kaneki
M
M
Weichselbaum
R
R
Davis
R J
RJ
Kufe
D
D
Kharbanda
S
S
D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D004789:Enzyme Activation; D006801:Humans; D008741:Methyl Methanesulfonate; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
D003561:Cytarabine; D008741:Methyl Methanesulfonate; D016315:Proto-Oncogene Proteins c-abl; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin