Selective activation of p38 MAPK cascade and mitotic arrest caused by low level oxidative stress

Apoptosis induced by high level oxidative stress accompanies diverse cellul ar biochemical events including activation of the stress signal cascades of JNK and NF-kappa B, We report here selective activation of p38 MAPK cascad e and mitotic arrest under a low level oxidative stress that lacks apoptosi s induction. U937 human lymphoid cells treated with low dose (0.02 mM) H2O2 rapidly caused p38 MAPK cascade activation detectable by phosphorylation o f MKK3/6, p38 MAPK, activating transcription factor-a, and cAMP-responsive element-binding protein, leaving the JNK and NF-KB cascades unaffected. The p38 kinase activation was sustained for 24 h under the low level stress co nditions and led to formation of polyploid nuclei. N-Acetyl-L-cysteine, a p recursor of anti-oxidant glutathione, canceled both p38 MAPK activation and abnormal cell cycle progression, whereas blockage of the kinase by specifi c inhibitor SB203580 allowed the appearance of apoptotic cells. Thus, mimic king the effects of nocodazole, the low level oxidative stimulus caused inh ibition of cell division in the M phase through p38 MAPK activation. The ki nase cascade may serve as a primary transducer of cytoplasmic oxidative sig nals 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.