Involvement of stress-activated MAP kinase p38 in p53-independent induction of p21/WAF1/Cip1 gene expression

A p53-independent increase in p21/WAF1/Cip1 gene expression is induced by anti-cancer agents such as trichostatin, actinomycin D and butyrate, and the signaling cascade of this induction was examined in cells stably transformed with a luciferase reporter under transcriptional control of the p21/WAF1/Cip1 gene. An inhibitor of stress-activated protein kinase p38 (SB203580) efficiently inhibited the induction, while PD98059, an inhibitor of MEK1, showed weaker inhibition. The dominant negative form of MKK6 inhibited the transcriptional activation of p21/WAF1/Cip1 gene in transient assay, whereas the dominant negative form of MKK4 did not affect it. Western blotting using antibodies against activated MAP kinases showed that butyrate, trichostatin and actinomycin D activated p38 in p53-defective human osteoblastic cells, but ERK1/2 and JNK activities were not increased significantly by these treatments. These results indicate that p38 kinase is the principal signaling molecule involved in the induction of p21/WAF1/Cip1 gene expression by butyrate, trichostatin and actinomycin D.