Apoptosis induced by high level oxidative stress accompanies diverse cellular biochemical events including activation of the stress signal cascades of JNK and NF-B. 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 elementbinding protein, leaving the JNK and NF-B 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 apoptosisinducing signals are transduced. This is the first report demonstrating that oxidative stress can participate in cell cycle control by induction of a signal cascade.

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p51/p63, a member of the tumor suppressor p53 gene family, is crucial for skin development. We describe here identification of ITGA3 encoding integrin ␣ 3 as a target of its trans-activating function, proposing that p51/p63 allows epidermal stem cells to express laminin receptor ␣ 3 ␤ 1 for anchorage to the basement membrane. When activated by genotoxic stress or overexpressed ectopically in non-adherent cells, p51/p63 transduced a phenotype to attach to extracellular matrices, which was accompanied by expression of ITGA3. Motifs matching the p53-binding consensus sequence were located in a scattered form in intron 1 of human ITGA3, and served as p51/p63-responsive elements in reporter assays. In addition to the trans-activating ability of the TA isoform, we detected a positive effect of the ⌬N isoform on ITGA3. The high level ␣ 3 production in human keratinocyte stem cells diminished upon elimination of p51/p63 by small interfering RNA or by Ca 2؉ -induced differentiation. Furthermore, a chromatin immunoprecipitation experiment indicated a physical interaction of p51/p63 with intron 1 of ITGA3. This study provides a molecular basis for the standing hypothesis that p51/p63 is essential for epidermal-mesenchymal interactions.