Bifunctional effects of a protein kinase inhibitor (H-7) on heat-induced p53-dependent WAF1 accumulation.
We have previously shown that heat shock induces p53-dependent WAF1 expression. To understand the role of protein kinases in the heat-induced p53-mediated signal transduction pathway, the effects of H-7, a serine/threonine kinase inhibitor, on WAF1 accumulation were investigated using two human glioblastoma cell lines differing in p53 status or their transfectants with various p53-expression vectors. Unexpectedly, H-7 alone induced p53-dependent WAF1 accumulation with a biphasic pattern depending on H-7 dose; i.e., low doses of H-7 induced the accumulation of both p53 and WAF1, whereas, a high dose of H-7 induced p53 but no WAF1 accumulation, suggesting that p53 accumulation and p53-dependent WAF1 expression are separable. Heat shock and H-7 induce p53-dependent WAF1 accumulation through different pathways as shown in A-172 cells stably expressing a temperature-sensitive mutant p53. However, our results show that these two pathways cross-talk with each other in the combined treatment of H-7 and heat shock studies. These findings indicate that inhibition of protein kinases can act as a novel stress to evoke the p53 pathway and that p53 activation by heat shock requires activation of yet unidentified protein kinases in vivo. The cross-talks between H-7 and heat shock in the p53 pathway provide the first evidence for the complex interactions between different stress signaling pathways in the modulation of p53 in vivo.
Wang
X
X
Biological Laboratory, Nara University of Education, Japan.
Takahashi
A
A
Ohnishi
K
K
Matsumoto
H
H
Suda
K
K
Ohnishi
T
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D005909:Glioblastoma; D006358:Hot Temperature; D006801:Humans; D007700:Kinetics; D017354:Point Mutation; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine