Hsp90 Gene Heat Induction Of Signal Transduction Pathways

Hsp90 is one of the most abundant proteins in the cytosol of eukaryotic cells, and its abundance is further increased by stress treatments. Hsp90 has stress-related as well as housekeeping functions, a suggestion that is substantiated by the identification of a variety of cellular targets for Hsp90. Hsp90 may have a general role in the refolding of the misfolded proteins that accumulate in response to various stress treatments and perhaps upon mutational alteration of proteins.Mammalian HSP90α and HSP90β are two major cellular proteins of the HSP90 subfamily and are highly homologous to each other at the protein level. The two HSP90s are found to be encoded by two individual genes, a and p. Induction of heat shock gene expression is mediated by specific heat shock transcription factors (HSFs), but the signaling pathways leading to activation of HSFs are poorly understood. To elucidate whether protein kinase C-responsive signaling pathways could be involved in the regulation of hsp90α and hsp90β gene expression, we have examined the effects of the protein kinase C inhibitor GF109203X and activator 12-O-tetradecanoyphorbol 13-acetate (TPA) on the heat-induced expression of hsp90α and hsp90β gene in Jurkat cells. We demonstrate the TPA treatment enhances both of hsp90α and hsp90β gene expression during heat stress, although TPA alone does not induce the heat shock response. This TPA-mediated enhancement can initially be detected as an accelerated acquisition of DNA binding and transcriptional activity of HSF1 resulting in elevated hsp90α and hsp90β mRNA. GF109203X has the opposite effect of heat induction of hsp90α and hsp90β genes to TPA.Phosphorylation of HSF1 might be one mechanism by which HSF1 function is modulated. Phosphorylation of transcription factors can occur through a number of different pathways in the cell, three of which are MAP ( mitogen-activated protein ) kinase pathways: the Raf/ERK ( extracellular-signal-regulated kinase) pathway, the MEKK/JNK( Jun N-terminal kinase )pathway and the p38 pathways. To elucidate whether these three kinds of MAPKs involved in the expressional control of hsp90α and hsp90β gene, we have done following experiments. Firstly, the phosphorylation...