Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50502 (Hip)
 7,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heat shock and other proteotoxic stresses cause accumulation of nonnative proteins that trigger activation of heat shock protein (Hsp) genes. A chaperone/Hsp functioning as repressor of heat shock transcription factor (HSF) could make activation of hsp genes dependent on protein unfolding. In a novel in vitro system, in which human HSF1 can be activated by nonnative protein, heat, and geldanamycin, addition of Hsp90 inhibits activation. Reduction of the level of Hsp90 but not of Hsp/c70, Hop, Hip, p23, CyP40, or Hsp40 dramatically activates HSF1. In vivo, geldanamycin activates HSF1 under conditions in which it is an Hsp90-specific reagent. Hsp90-containing HSF1 complex is present in the unstressed cell and dissociates during stress. We conclude that Hsp90, by itself and/or associated with multichaperone complexes, is a major repressor of HSF1.
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PMID:Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. 972 90

Rapid and transient activation of heat shock genes in response to stress is mediated in eukaryotes by the heat shock transcription factor HSF1. It is well established that cells maintain a dynamic equilibrium between inactive HSF1 monomers and transcriptionally active trimers, but little is known about the mechanism linking HSF1 to reception of various stress stimuli or the factors controlling oligomerization. Recent reports have revealed that HSP90 regulates key steps in the HSF1 activation-deactivation process. Here, we tested the hypothesis that components of the HSP90 chaperone machine, known to function in the folding and maturation of steroid receptors, might also participate in HSF1 regulation. Mobility supershift assays using antibodies against chaperone components demonstrate that active HSF1 trimers exist in a heterocomplex with HSP90, p23, and FKBP52. Functional in vivo experiments in Xenopus oocytes indicate that components of the HSF1 heterocomplex, as well as other components of the HSP90 cochaperone machine, are involved in regulating oligomeric transitions. Elevation of the cellular levels of cochaperones affected the time of HSF1 deactivation during recovery: attenuation was delayed by immunophilins, and accelerated by HSP90, Hsp/c70, Hip, or Hop. In immunotargeting experiments with microinjected antibodies, disruption of HSP90, Hip, Hop, p23, FKBP51, and FKBP52 delayed attenuation. In addition, HSF1 was activated under nonstress conditions after immunotargeting of HSP90 and p23, evidence that these proteins remain associated with HSF1 monomers and function in their repression in vivo. The remarkable similarity of HSF1 complex chaperones identified here (HSP90, p23, and FKBP52) and components in mature steroid receptor complexes suggests that HSF1 oligomerization is regulated by a foldosome-type mechanism similar to steroid receptor pathways. The current evidence leads us to propose a model in which HSF1, HSP90 and p23 comprise a core heterocomplex required for rapid conformational switching through interaction with a dynamic series of HSP90 subcomplexes.
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PMID:Multiple components of the HSP90 chaperone complex function in regulation of heat shock factor 1 In vivo. 1056 29

The U-box E3 ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein) binds Hsp90 and/or Hsp70 via its tetratricopeptide repeat (TPR), facilitating ubiquitination of the chaperone-bound client proteins. Mechanisms that regulate the activity of CHIP are, at present, poorly understood. We previously reported that Ca(2+)/S100 proteins directly associate with the TPR proteins, such as Hsp70/Hsp90-organizing protein (Hop), kinesin light chain, Tom70, FKBP52, CyP40, and protein phosphatase 5 (PP5), leading to the dissociation of the interactions of the TPR proteins with their target proteins. Therefore, we have hypothesized that Ca(2+)/S100 proteins can interact with CHIP and regulate its function. GST pulldown assays indicated that Ca(2+)/S100A2 and S100P bind to the TPR domain and lead to interference with the interactions of CHIP with Hsp70, Hsp90, HSF1, and Smad1. In vitro ubiquitination assays indicated that Ca(2+)/S100A2 and S100P are efficient and specific inhibitors of CHIP-mediated ubiquitination of Hsp70, Hsp90, HSF1, and Smad1. Overexpression of S100A2 and S100P suppressed CHIP-chaperone complex-dependent mutant p53 ubiquitination and degradation in Hep3B cells. The association of the S100 proteins with CHIP provides a Ca(2+)-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.
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PMID:Ca2+/S100 proteins act as upstream regulators of the chaperone-associated ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein). 2334 57