p38 mitogen-activated protein kinase promotes cell survival in response to DNA damage but is not required for the G(2) DNA damage checkpoint in human cancer cells.
p38 mitogen-activated protein kinase (MAPK) is rapidly activated by stresses and is believed to play an important role in the stress response. While Chk1 is known to mediate G(2) DNA damage checkpoint control, p38 was also reported to have an essential function in this checkpoint control. Here, we have investigated further the roles of p38 and Chk1 in the G(2) DNA damage checkpoint in cancer cells. We find that although p38 activation is strongly induced by DNA damage, its activity is not required for the G(2) DNA damage checkpoint. In contrast, Chk1 kinase is responsible for the execution of G(2) DNA damage checkpoint control in p53-deficient cells. The inhibition of p38 activity has no effect on Chk1 activation and gamma-H2AX expression. Global gene expression profiling of cancer cells in response to tumor necrosis factor alpha (TNF-alpha) revealed that p38 plays a strong prosurvival role through the coordinated downregulation of proapoptotic genes and upregulation of prosurvival genes. We show that the inhibition of p38 activity during G(2) DNA damage checkpoint arrest triggers apoptosis in a p53-independent manner with a concurrent decrease in the level of Bcl2 family proteins. Our results suggest that although p38 MAPK is not required for the G(2) DNA damage checkpoint function, it plays an important prosurvival role during the G(2) DNA damage checkpoint response through the upregulation of the Bcl2 family proteins.
Phong
Mark S
MS
Lilly Singapore Center for Drug Discovery, Pte Ltd. (Eli Lilly & Company), Singapore, Republic of Singapore.
Van Horn
Robert D
RD
Li
Shuyu
S
Tucker-Kellogg
Gregory
G
Surana
Uttam
U
Ye
Xiang S
XS
D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D015536:Down-Regulation; D006801:Humans; D009369:Neoplasms; D009423:Nervous System Neoplasms; D011494:Protein Kinases / Q000378:metabolism / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000494:pharmacology
D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases