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Selective activation of p38 MAPK cascade and mitotic arrest caused by low level oxidative stress
1Department 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
Abstract:
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.
Insights
Low-level oxidative stress selectively activates the p38 mitogen-activated protein kinase (MAPK) cascade, causing cell cycle arrest without apoptosis. This highlights oxidative stress
Area of Science:
- Cell Biology
- Molecular Biology
- Stress Signaling
Background:
- High-level oxidative stress induces apoptosis via JNK and NF-kappaB signaling.
- The role of low-level oxidative stress in cellular responses remains less understood.
- Cell cycle regulation is crucial for maintaining genomic stability.
Purpose of the Study:
- To investigate the cellular and molecular effects of low-level oxidative stress.
- To determine the specific signaling pathways activated by mild oxidative conditions.
- To elucidate the impact of oxidative stress on cell cycle progression.
Main Methods:
- Treatment of U937 human lymphoid cells with low-dose hydrogen peroxide (H2O2).
- Analysis of mitogen-activated protein kinase (MAPK) cascade activation (p38, JNK, NF-kappaB).
- Assessment of cell cycle progression, nuclear morphology, and apoptosis.
- Use of N-Acetyl-l-cysteine and SB203580 to modulate oxidative stress and p38 activity.
Main Results:
- Low-dose H2O2 selectively activated the p38 MAPK cascade, evidenced by MKK3/6, p38 MAPK, ATF-2, and CREB phosphorylation.
- JNK and NF-kappaB cascades remained unaffected, and apoptosis was not induced.
- Sustained p38 activation led to mitotic arrest and polyploid nuclei formation, mimicking nocodazole effects.
- N-Acetyl-l-cysteine reversed p38 activation and cell cycle abnormalities; SB203580 induced apoptosis.
Conclusions:
- Low-level oxidative stress triggers a distinct signaling pathway involving p38 MAPK activation.
- This pathway mediates cell cycle arrest in the M phase, independent of apoptosis.
- The p38 MAPK cascade acts as a critical transducer of oxidative signals for cell cycle control.