De-repression of heat shock transcription factor-1 in interleukin-6- treated hepatocytes is mediated by downregulation of glycogen synthase kinase 3beta and MAPK/ERK-1
| Autor: | Stephen J, Wigmore, Kathryn, Sangster, Stephen J, McNally, Ewen M, Harrison, James A, Ross, Kenneth C H, Fearon, O James, Garden |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cytoplasm
Transcription Genetic Morpholines Down-Regulation Glycogen Synthase Kinase 3 Heat Shock Transcription Factors Humans Protein Isoforms HSP70 Heat-Shock Proteins RNA Messenger Phosphorylation Protein Structure Quaternary Cells Cultured Phosphoinositide-3 Kinase Inhibitors Cell Nucleus Glycogen Synthase Kinase 3 beta Mitogen-Activated Protein Kinase 3 Interleukin-6 Hyperthermia Induced Up-Regulation Androstadienes DNA-Binding Proteins Enzyme Activation Protein Transport Chromones Hepatocytes RNA Interference Wortmannin Proto-Oncogene Proteins c-akt Transcription Factors |
| Zdroj: | International journal of molecular medicine. 19(3) |
| ISSN: | 1107-3756 |
| Popis: | Expression of inducible heat shock protein (HSP70) requires activation of heat shock transcription factor-1 (HSF-1). Recent evidence suggests that interleukin-6 (IL-6) can modify the response of HSF-1 to heat. We hypothesized that IL-6 would prime the HSP response by causing de-repression of HSF-1 resulting in augmented HSP expression in stressed cells. In this study we show that IL-6 has no direct effect on HSP70 expression at 37 degrees C but does augment HSP70 expression in response to heat. IL-6 treatment decreased active MAPK/pERK and glycogen synthase kinase 3beta (GSK3beta) expression and GSK3beta kinase activity. In IL-6-treated cells, monomeric HSF-1 accumulated in the cytoplasm and nucleus, bound DNA but was transcriptionally inactive. On exposure to heat shock this modified monomer assumed the transcriptionally active phenotype with trimerization and hyperphosphorylation evident. The increased induction of HSP70 in IL-6 and heat-treated cells was inhibited using PI3-kinase inhibitors or Akt inhibition and was HSF-1 dependent. IL-6, via the PI3-kinase/Akt pathway leads to inhibition of the repressive kinases MAPK/pERK and GSK3beta, and this converts inactive HSF-1 to an intermediate DNA-binding form augmenting transcriptional activation in the presence of a second stressor. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|