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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cdc37 is a molecular chaperone closely associated with the folding of protein kinases. Results from studies using a yeast model system showed that it was also important for activation of the human androgen receptor (AR). Based on results from the yeast model system (Fliss, A. E., Fang, Y., Boschelli, F., and Caplan, A. J. (1997) Mol. Biol. Cell 8, 2501-2509), we initiated studies to address whether AR and Cdc37 interact with each other in animal cell systems. Our results show that Cdc37 binds to AR but not to glucocorticoid receptors (GR) synthesized in rabbit reticulocyte lysates. This binding occurs via the ligand-binding domain of the AR in a manner that is partially dependent on Hsp90 and the presence of hormone. Further studies using the yeast system showed that Cdc37 is not interchangeable with Hsp90, suggesting that it functions at a distinct step in the activation pathway. Expression of a dominant negative form of Cdc37 in animal cells down-regulates full-length AR but has very little effect on an AR truncation lacking the ligand-binding domain or full-length GR. These results reveal differences in the mechanisms by which AR and GR become active transcription factors and strengthen the notion that Cdc37 has a wider range of polypeptide clients than was realized previously.
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PMID:Functional interaction of human Cdc37 with the androgen receptor but not with the glucocorticoid receptor. 1108 88

Two-component signal transduction (TCST) systems are the principal means for coordinating responses to environmental changes in bacteria as well as some plants, fungi, protozoa, and archaea. These systems typically consist of a receptor histidine kinase, which reacts to an extracellular signal by phosphorylating a cytoplasmic response regulator, causing a change in cellular behavior. Although several model systems, including sporulation and chemotaxis, have been extensively studied, the evolutionary relationships between specific TCST systems are not well understood, and the ancestry of the signal transduction components is unclear. Phylogenetic trees of TCST components from 14 complete and 6 partial genomes, containing 183 histidine kinases and 220 response regulators, were constructed using distance methods. The trees showed extensive congruence in the positions of 11 recognizable phylogenetic clusters. Eukaryotic sequences were found almost exclusively in one cluster, which also showed the greatest extent of domain variability in its component proteins, and archaeal sequences mainly formed species-specific clusters. Three clusters in different parts of the kinase tree contained proteins with serine-phosphorylating activity. All kinases were found to be monophyletic with respect to other members of their superfamily, such as type II topoisomerases and Hsp90. Structural analysis further revealed significant similarity to the ATP-binding domain of eukaryotic protein kinases. TCST systems are of bacterial origin and radiated into archaea and eukaryotes by lateral gene transfer. Their components show extensive coevolution, suggesting that recombination has not been a major factor in their differentiation. Although histidine kinase activity is prevalent, serine kinases have evolved multiple times independently within this family, accompanied by a loss of the cognate response regulator(s). The structural and functional similarity between TCST kinases and eukaryotic protein kinases raises the possibility of a distant evolutionary relationship.
Mol Biol Evol 2000 Dec
PMID:Evolution of two-component signal transduction. 1111 Sep 12

Large peptidyl-prolyl cis/trans isomerases (PPIases) are important components of the Hsp90 chaperone complex. In mammalian cells, either Cyp40, FKBP51 or FKBP52 is incorporated into these complexes. It has been suggested that members of this protein family exhibit both prolyl isomerase and chaperone activity. Here we define the structural and functional properties of the three mammalian large PPIases. We find that in all cases two PPIase monomers bind to an Hsp90 dimer. However, the affinities of the PPIases are different with FKBP52 exhibiting the strongest interaction and Cyp40 the weakest. Furthermore, in the mammalian system, in contrast to the yeast system, the catalytic activity of prolyl isomerization corresponds well to that of the respective small PPIases. Interestingly, Cyp40 and FKBP51 are the more potent chaperones. Thus, it seems that both the affinity for Hsp90 and the differences in their chaperone properties, which may reflect their interaction with the non-native protein in the Hsp90 complex, are critical for the selective incorporation of a specific large PPIase.
J Mol Biol 2001 May 11
PMID:Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40. 1135 Jan 75

Recent studies on Drosophila and Caenorhabditis elegans indicate that increases in stress resistance result in a longer chronological life span, an effect that must operate primarily on the postmitotic tissues of the adult. Stress resistance can be increased through decreases in Hsp90 chaperone activity, since Hsp90 acts to downregulate the activity of heat shock transcription factor. This study investigated whether the increases in stress resistance associated with reduced Hsp90 chaperone activity influence ageing in the budding yeast Saccharomyces cerevisiae, ageing being measured either as the replicative (nonchronological) senescence of budding cells or as the chronological ageing of non-dividing (stationary phase) cultures. Overactivation of the heat shock response caused no slowing of replicative senescence. In some situations though it was associated with a longer chronological life span of stationary cells, the yeast equivalent of the postmitotic state. This is consistent with the idea that stress resistance exerts its life span-extending effects primarily in postmitotic cells and tissues.
Mol Genet Genomics 2001 Apr
PMID:Increasing Saccharomyces cerevisiae stress resistance, through the overactivation of the heat shock response resulting from defects in the Hsp90 chaperone, does not extend replicative life span but can be associated with slower chronological ageing of nondividing cells. 1136 36

Cdc13 is a Saccharomyces cerevisiae protein that binds to telomeric single-stranded DNA and regulates telomerase activity. Stnl has been shown by two-hybrid analysis to form a physical complex with Cdc13. Temperature-sensitive mutations in CDC13 and STN1, which are both essential genes, activate a DNA damage-dependent checkpoint which is the cause of the arrest seen in the mutant strains. The stn1-13 mutation induces dramatic telomere elongation which is telomerase dependent, as shown here. Additional mutants for STN1, which show a tighter arrest phenotype than stn1-13, were generated in order to perform genetic screens aiming at uncovering new regulators of telomerase. HSC82, which encodes a conserved molecular chaperone of the Hsp90 family, was thus isolated as a high-dosage suppressor of a temperature-sensitive mutation in STN1. Overexpression of HSC82 also partially suppressed the growth defect of cdc13-1 cells. Overexpression of HSC82 was found to correct the telomeric defect associated with stn1 mutations. Shortening of telomeres was also observed in wild-type cells upon overexpression of HSC82, or of its temperature-inducible homologue, HSP82. These results identify Hsc82/Hsp82 as potential regulators of telomerase in yeast cells.
Mol Genet Genomics 2001 Mar
PMID:Hsp90 levels affect telomere length in yeast. 1137 Aug 58

Huntington's disease (HD) is a progressive neurodegenerative disorder with no effective treatment. Geldanamycin is a benzoquinone ansamycin that binds to the heat shock protein Hsp90 and activates a heat shock response in mammalian cells. In this study, we show by using a filter retardation assay and immunofluorescence microscopy that treatment of mammalian cells with geldanamycin at nanomolar concentrations induces the expression of Hsp40, Hsp70 and Hsp90 and inhibits HD exon 1 protein aggregation in a dose-dependent manner. Similar results were obtained by overexpression of Hsp70 and Hsp40 in a separate cell culture model of HD. This is the first demonstration that huntingtin protein aggregation in cells can be suppressed by chemical compounds activating a specific heat shock response. These findings may provide the basis for the development of a novel pharmacotherapy for HD and related glutamine repeat disorders.
Hum Mol Genet 2001 Jun 01
PMID:Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. 1140 12

The GR is a hormone-activated transcription factor that acts to regulate specific gene expression. In the absence of hormone, the GR and other steroid receptors have been shown to form complexes with several mammalian heat shock proteins. As heat shock proteins are produced by cells as an adaptive response to stress, speculation has existed that communication between the heat shock and glucocorticoid hormone signal pathways must exist. Only recently has evidence to support this hypothesis been reported. In almost all cases, the evidence has been of an ability of heat shock to cause a potentiation of the glucocorticoid hormone response. In this proposal, evidence is now presented that heat shock signaling can, in turn, be regulated by glucocorticoids. In mouse L929 cells stably expressing a chloramphenicol acetyltransferase reporter controlled by the human heat shock protein70 promoter and containing known binding sites for heat shock transcription factor 1 treatment with glucocorticoid agonist (dexamethasone) results in a dose-dependent decrease of stress-induced chloramphenicol acetyltransferase gene expression. In these cells, inhibition of heat shock protein70 promoter activity by dexamethasone was completely blocked by GR antagonist (RU486). Similar treatment of L929 cells stably expressing a chloramphenicol acetyltransferase reporter under the control of the constitutively active SV40 promoter showed no such inhibition by dexamethasone. More importantly, dexamethasone was also found to inhibit heat shock-induced expression of the major heat shock proteins-heat shock proteins70, 90, and 110. Thus, the inhibitory effect of dexamethasone appears to apply to most, if not all, heat shock transcription factor 1-regulated genes. Although dexamethasone did not prevent the DNA-binding function of heat shock-activated heat shock transcription factor 1, it did inhibit a constitutively active mutant of human heat shock transcription factor 1 under nonstress conditions, suggesting that dexamethasone repression of heat shock transcription factor 1 was primarily through an inhibition of heat shock transcription factor 1 transcription enhancement activity. To more accurately characterize the stage of GR signaling responsible for inhibition of heat shock transcription factor 1, a series of Chinese hamster ovary cells containing either no GR, wild-type mouse GR, or single-point mutations of GR were employed. Dexamethasone inhibition of heat shock-induced heat shock transcription factor 1 activity was observed in the presence of wild-type GR, but not in Chinese hamster ovary cells lacking GR, suggesting that signaling cascades other than GR were not involved in this effect of dexamethasone. Consistent with this conclusion was the observation that dexamethasone had no effect on activity of the MAPKs (ERK1, ERK2, or c-jun N-terminal kinase), which are known to negatively regulate heat shock transcription factor 1. Dexamethasone inhibition of heat shock transcription factor 1 was not seen in Chinese hamster ovary cells expressing GR defective for DNA-binding function. Moreover, dissociation of GR/Hsp90/Hsp70 complexes was observed in response to hormone for both the wild-type and DNA binding-defective forms of GR, demonstrating that release of Hsp90 or Hsp70 (both of which are known to keep heat shock transcription factor 1 in its inactive state) could be ruled out as a potential mechanism. Thus, it appears that GR-mediated transactivation or transrepression is required for the inhibitory effect of dexamethasone on heat shock transcription factor 1 activity. Taken as a whole, these results provide evidence for a novel mechanism of cross-talk in which signaling by the GR can attenuate the heat shock response in cells through an inhibition of the transcription enhancement activity of HSF1.
Mol Endocrinol 2001 Aug
PMID:Inhibition of heat shock transcription factor by GR. 1146 62

The highly abundant molecular chaperone Hsp90 functions with assistance from auxiliary factors, collectively referred to as Hsp90 cochaperones, and the Hsp70 system. Hsp104, a molecular chaperone required for stress tolerance and for maintenance of [psi(+)] prions in the budding yeast Saccharomyces cerevisiae, appears to collaborate only with the Hsp70 system. We now report that several cochaperones previously thought to be dedicated to Hsp90 are shared with Hsp104. We show that the Hsp90 cochaperones Sti1, Cpr7, and Cns1, which utilize tetratricopeptide repeat (TPR) domains to interact with a common surface on Hsp90, form complexes with Hsp104 in vivo and that Sti1 and Cpr7 interact with Hsp104 directly in vitro. The interaction is Hsp90 independent, as further emphasized by the fact that two distinct TPR domains of Sti1 are required for binding Hsp90 and Hsp104. In a striking parallel to the sequence requirements of Hsp90 for binding TPR proteins, binding of Sti1 to Hsp104 requires a related acidic sequence at the C-terminal tail of Hsp104. While Hsp90 efficiently sequesters the cochaperones during fermentative growth, respiratory conditions induce the interaction of a fraction of Hsp90 cochaperones with Hsp104. This suggests that cochaperone sharing may favor adaptation to altered metabolic conditions.
Mol Cell Biol 2001 Nov
PMID:Hsp104 interacts with Hsp90 cochaperones in respiring yeast. 1160 93

In Saccharomyces cerevisiae, heme directly mediates the effects of oxygen on transcription through the heme activator protein Hap1. In the absence of heme, Hap1 is bound by at least four cellular proteins, including Hsp90 and Ydj1, forming a higher-order complex, termed HMC, and its activity is repressed. Here we purified the HMC and showed by mass spectrometry that two previously unidentified major components of the HMC are the Ssa-type Hsp70 molecular chaperone and Sro9 proteins. In vivo functional analysis, combined with biochemical analysis, strongly suggests that Ssa proteins are critical for Hap1 repression in the absence of heme. Ssa may repress the activities of both Hap1 DNA-binding and activation domains. The Ssa cochaperones Ydj1 and Sro9 appear to assist Ssa in Hap1 repression, and only Ydj1 residues 1 to 172 containing the J domain are required for Hap1 repression. Our results suggest that Ssa-Ydj1 and Sro9 act together to mediate Hap1 repression in the absence of heme and that molecular chaperones promote heme regulation of Hap1 by a mechanism distinct from the mechanism of steroid signaling.
Mol Cell Biol 2001 Dec
PMID:The Hsp70-Ydj1 molecular chaperone represses the activity of the heme activator protein Hap1 in the absence of heme. 1168 85

The differentiation of Leishmania parasites from the insect stage, the promastigote, toward the pathogenic mammalian stage, the amastigote, is triggered primarily by the rise in ambient temperature encountered during the insect-to-mammal transmission. We show here that inactivation of heat shock protein (Hsp) 90, with the use of the drugs geldanamycin or radicicol, mimics transmission and induces the differentiation from the promastigote to the amastigote stage. Geldanamycin also induces a growth arrest of cultured promastigotes that can be forestalled by overexpression of the cytoplasmic Hsp90. Moreover, we demonstrate that Hsp90 serves as a feedback inhibitor of the cellular heat shock response in Leishmania. Our results are consistent with Hsp90 homeostasis serving as cellular thermometer for these primitive eukaryotes, controlling both the heat shock response and morphological differentiation.
Mol Biol Cell 2001 Nov
PMID:Heat shock protein 90 homeostasis controls stage differentiation in Leishmania donovani. 1169 68


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