Disease relevance of Hspca

• Hsp90 regulation of endothelial nitric oxide synthase contributes to vascular control in portal hypertension [1].
• Increased resistance to myocardial ischemia in the Brown Norway vs. Dahl S rat: role of nitric oxide synthase and Hsp90 [2].
• Heat shock protein 70 (Hsp70) and 90 (Hsp90) are involved in ischemia tolerance, and were not colocalized with TUNEL in the immunohistochemical staining, suggesting an antiapoptotic role of Hsp's. To determine the effect of testosterone on MCAO-induced Hsp70 and -90 expression, a testosterone replacement or withdrawal paradigm was used [3].
• After exposure of the animals to the heat stress, the level of cytosolic Hsp90 increased, while its ratio to apo-receptor within non-activated GR heterooligomeric complexes remained unaltered [4].
• Glucocorticoid receptor interaction with Hsp90 remains unaltered after whole body hyperthermia [4].

High impact information on Hspca

• Propranolol decreased NOS activity by 47% and eNOS and Hsp90 expression by 75% and 72%, respectively [5].
• We find that the alphaGDI-chaperone complex is dissociated in response to Ca(2+)-induced neurotransmitter release, that chaperone complex dissociation is sensitive to the Hsp90 inhibitor geldanamycin (GA) and that GA inhibits the ability of alphaGDI to recycle Rab3A during neurotransmitter release [6].
• We propose that alphaGDI interacts with a specialized membrane-associated Rab recycling Hsp90 chaperone system on the vesicle membrane to coordinate the Ca(2+)-dependent events triggering Rab-GTP hydrolysis with retrieval of Rab-GDP to the cytosol [6].
• BDNF could stimulate tumor cell proliferation in a Hsp90-dependent manner [7].
• Here we show that lowering ATP concentration by inhibiting glycolysis or mitochondrial respiration in isolated myocytes triggers rapid dissociation of Hsp90 from ErbB2 and degradation of ErbB2 along with other client proteins [8].

Biological context of Hspca

• We performed a systematic analysis of the nucleotide binding specificity of the Hsp90 nucleotide binding sites [9].
• The role of Hsp90N, a new member of the Hsp90 family, in signal transduction and neoplastic transformation [10].
• In the perfused mesenteric vasculature of normal animals, geldanamycin (GA), a specific inhibitor of Hsp90 signaling, attenuates ACh-dependent vasodilation but does not affect vasodilation in response to sodium nitroprusside [1].
• These studies suggest that Hsp90 can act as a signaling mediator of NO-dependent responses in the mesenteric circulation and indicate that the excessive NO production observed in portal hypertension is mediated in part through Hsp90 signaling [1].
• Ligand interactions in the adenosine nucleotide-binding domain of the Hsp90 chaperone, GRP94. I. Evidence for allosteric regulation of ligand binding [11].

Anatomical context of Hspca

• In the optic nerve, the relative difference in immunoreactivity for the two Hsps was reversed, with Hsp25 being considerably greater than Hsp90 [12].
• Similar to the optic nerve, the corneal epithelium showed greater staining for Hsp25 than for Hsp90, and basal cells contained the highest levels of immunoreactivity for both Hsps [12].
• METHODS: Histochemical and immunoblotted signals for the NOS isoforms, caveolin and Hsp90 were compared in left ventricle (LV) and aortic or mesenteric vessels between spontaneously hypertensive rats (SHR; 18 and 63 weeks old) and age-matched normotensive Wistar-Kyoto (WKY) rats [13].
• In situ hybridization analysis indicated that Hsp90 mRNA was prominent in gonocytes, where it was increased following phytoestrogen exposure, whereas bisphenol A induced a more generalized increase throughout the testis [14].
• Constitutively expressed heat shock proteins Hsp90, Hsc70, Hsp60, and Hsp40 and a range of neurotransmitter receptors are present in lipid rafts isolated from rat forebrain and cerebellum [15].

Associations of Hspca with chemical compounds

• These results demonstrate that prenatal estrogen exposure specifically affects Hsp90 expression in gonocytes [14].
• Prenatal exposure to the estrogenic compounds diethylstilbestrol, bisphenol A, genistein, and coumestrol led to significantly increased Hsp90 mRNA levels in testis, but not p23 and Cyp40 [14].
• In isolated rat hearts, geldanamycin, a blocker of Hsp90-dependent translocation of proteins to the inner mitochondrial membrane through the TOM pathway, rapidly (15 minutes) reduced mitochondrial Cx43 content by approximately one-third in the absence or presence of diazoxide [16].
• Arsenite induced expression of heat shock proteins Hsp72, Hsp32, and Hsp90, but endothelial nitric oxide synthase expression was not changed [17].
• Hsp90 association with glucocorticoid receptors (GRs) is required for steroid binding [18].

Regulatory relationships of Hspca

• The Hsp90 inhibitor geldanamycin blocked flow-induced eNOS translocation to the apical membrane (n = 6) [19].
• Its cysteine groups participate in the interactions of Hsp90 with the heme-regulated eIF-2alpha kinase and molybdate, a stabilizer of Hsp90-protein complexes [20].

Other interactions of Hspca

• Conversely, aortic caveolin-1 and -3 were decreased in SHR, whereas Hsp90 remained unchanged [13].
• Glucocorticoid hormone receptor exists in the cytoplasm of target cells in the form of dynamic multiprotein heterocomplexes with heat shock proteins Hsp90 and Hsp70, and additional components of the molecular chaperone machinery [21].
• A heat shock protein complex isolated from rabbit reticulocyte lysate can reconstitute a functional glucocorticoid receptor-Hsp90 complex [22].
• Oxidizing conditions impair the chaperone activity of Hsp90 toward citrate synthase [20].
• In activated cells, cPGES phosphorylation occurred in parallel with increased cPGES enzymic activity and PGE2 production from exogenous and endogenous arachidonic acid, and these processes were facilitated by Hsp90 (heat-shock protein 90), a molecular chaperone that formed a tertiary complex with cPGES and CK-II [23].

Analytical, diagnostic and therapeutic context of Hspca

• The 90-kDa heat shock protein (Hsp90), the target of the ansamycin class of anti-cancer drugs, is required for the conformational activation of a specific group of signal transducers, including Raf-1 [10].
• The stress response of PC12 cells was characterized by evaluating the production of heat shock proteins of the 70 kDa (Hsp70), 60 kDa (Hsp60) and 90 kDa (Hsp90) families by western blot analysis [24].
• GA reduced co-immunoprecipitation of HSF1 with Hsp90 in brain tissue homogenates, promoted HSE-binding of HSF in brain nuclear extracts using gel shift assays, and increased luciferase reporter gene transcription for the Hsp70 promoter in PC12 cells [25].
• Hsp90alpha and Hsp90beta upregulation induced by a low-sodium diet together with redistribution in thick ascending limb cells suggests that Hsp90 plays a role in the modulation of sodium reabsorption under these circumstances [26].
• In this study, we examined the microinjection of A beta 42 in the presence or absence of Hsp90 into the rat hippocampus in vivo [27].

References