A novel role of p38 alpha MAPK in mitotic progression independent of its kinase activity.
Activation of p38alpha MAPK triggers G2/M checkpoint, thus inhibiting cell proliferation. In this study we found that depletion of p38alpha by RNAi also inhibited cell proliferation and caused mitotic arrest. However, treatment with selective small molecule p38 kinase inhibitors had no effect on cell cycle progression, even though the p38 kinase was completely inhibited, revealing p38alpha functions that are independent of its kinase activity. Indeed, ectopic expression of a kinase negative p38alpha rescued the lethality caused by RNAi-depletion of the endogenous p38alpha, thus providing further evidence for a kinase-independent function of p38alpha. In addition, we showed that overexpression of the wild type or kinase-negative p38alpha also strongly inhibited cell proliferation, similarly as RNAi depletion of p38alpha. Together the results demonstrate that, in addition to its kinase-dependent functions, such as in activation of G2/M checkpoint, p38alpha also has an essential, kinase-independent function.
Fan
Li
L
Cancer Research Division, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Yang
Xianlin
X
Du
Jian
J
Marshall
Mark
M
Blanchard
Kerry
K
Ye
Xiang
X
D000818:Animals; D002455:Cell Division / Q000502:physiology; D049109:Cell Proliferation; D016195:G2 Phase / Q000502:physiology; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology*; D008938:Mitosis / Q000502:physiology*; D041681:NIH 3T3 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference
D006131:Growth Inhibitors; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14