Involvement of c-Jun NH(2)-terminal kinase pathway in differential regulation of heat shock proteins by anticancer drugs.
In the present study, we examined the modulation of heat shock factor 1 (HSF1) activity and expression of heat shock proteins (HSPs) after exposure to anticancer drugs. Anticancer drugs induced HSF1 DNA-binding activity, and this was followed by an increase of mitochondrial HSP75 and HSP60 levels and concurrent decrease of cytoplasmic HSP70 levels. Unlike heat shock-induced full phosphorylation, HSF1 was partially phosphorylated after exposure to vincristine, and this result was tightly correlated with the kinetics of JNK/SAPK activation, and up-regulation of mitochondrial HSP75 level and concurrent down-regulation of HSP70. Furthermore, the dominant-negative mutant of SEK1 blocked the phosphorylation of HSF1 and up-regulation of mitochondrial HSP75 in response to vincristine or vinblastine. These data suggest that anticancer drugs regulate the HSF1 transcriptional activity differently from heat shock, and JNK/SAPK pathway appears to be involved in anticancer drug-induced HSF1 phosphorylation and consequently differential regulation of mitochondrial HSP75 and HSP60 and cytoplasmic HSP70.
Kim
S H
SH
College of Medicine, Pusan National University, Pusan, 602-739, Korea.
Kim
D
D
Jung
G S
GS
Um
J H
JH
Chung
B S
BS
Kang
C D
CD
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D011485:Protein Binding; D014157:Transcription Factors; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D014157:Transcription Factors; D001761:Bleomycin; D014750:Vincristine; D014747:Vinblastine; D004317:Doxorubicin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases