Selective activation of p38 MAPK cascade and mitotic arrest caused by low level oxidative stress.
Apoptosis induced by high level oxidative stress accompanies diverse cellular biochemical events including activation of the stress signal cascades of JNK and NF-kappaB. We report here selective activation of p38 MAPK cascade and mitotic arrest under a low level oxidative stress that lacks apoptosis induction. U937 human lymphoid cells treated with low dose (0.02 mm) H(2)O(2) rapidly caused p38 MAPK cascade activation detectable by phosphorylation of MKK3/6, p38 MAPK, activating transcription factor-2, and cAMP-responsive element-binding protein, leaving the JNK and NF-kappaB cascades unaffected. The p38 kinase activation was sustained for 24 h under the low level stress conditions and led to formation of polyploid nuclei. N-Acetyl-l-cysteine, a precursor of anti-oxidant glutathione, canceled both p38 MAPK activation and abnormal cell cycle progression, whereas blockage of the kinase by specific inhibitor SB203580 allowed the appearance of apoptotic cells. Thus, mimicking the effects of nocodazole, the low level oxidative stimulus caused inhibition of cell division in the M phase through p38 MAPK activation. The kinase cascade may serve as a primary transducer of cytoplasmic oxidative signals to nucleus for stress-relieving gene expression and cell cycle control before apoptosis-inducing signals are transduced. This is the first report demonstrating that oxidative stress can participate in cell cycle control by induction of a signal cascade.
Kurata
S
S
Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. kushbgen@mri.tmd.ac.jp
D000111:Acetylcysteine / Q000494:pharmacology; D051697:Activating Transcription Factor 1; D051698:Activating Transcription Factor 2; D002467:Cell Nucleus; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008938:Mitosis; D018384:Oxidative Stress; D011123:Polyploidy; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases
C497105:ATF2 protein, human; D051697:Activating Transcription Factor 1; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000111:Acetylcysteine