Disease relevance of Hsp90ab1

• Androgen receptor (AR), a pathogenic gene product in spinal and bulbar muscular atrophy (SBMA), is one of the Hsp90 client proteins [1].
• In this study, we investigated the effect as well as the molecular mechanism of geldanamycin (GA), an inhibitor of Hsp90, on 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a mouse model of Parkinson disease [2].
• These Hsp90 inhibitors, however, had no effect on Staphylococcus aureus Cowan strain 1-induced IL-12 production from either the murine spleen cells or macrophages [3].
• Pretreatment with any of the three Hsp90 inhibitors geldanamycin, radicicol, and herbimycin A resulted in a dose-dependent suppression of cytokine production from the spleen cells and macrophages and of NO from macrophages stimulated with CpG ODN or E. coli DNA [3].
• Comparison of 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) and 17-allylamino-17-demethoxygeldanamycin (17AAG) in vitro: effects on Hsp90 and client proteins in melanoma models [4].

High impact information on Hsp90ab1

• We examined the therapeutic effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a potent Hsp90 inhibitor, and its ability to degrade polyglutamine-expanded mutant AR [1].
• 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration [1].
• Hsp90 chaperones protein folding in vitro [5].
• The heat-shock protein Hsp90 is the most abundant constitutively expressed stress protein in the cytosol of eukaryotic cells, where it participates in the maturation of other proteins, modulation of protein activity in the case of hormone-free steroid receptors, and intracellular transport of some newly synthesized kinases [5].
• Modulating molecular chaperone Hsp90 functions through reversible acetylation [6].

Chemical compound and disease context of Hsp90ab1

• EXPERIMENTAL DESIGN: The effect of 17-AAG on the expression of Hsp90 regulated signaling proteins in prostate cancer cells and xenografts was determined [7].
• EXPERIMENTAL DESIGN: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin (17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts [8].
• The detergent Nonidet P40 was used to solubilize tumor-specific transplantation antigens (TSTA) from crude membranes obtained from dissociated cells of simian virus 40-induced sarcoma of BALB/c mice [9].
• The nonionic detergent octyl-beta-D-glucopyranoside (C8Glu) was used to extract immunogenic tumor-specific transplantation antigen (TSTA) from intact cells and purified plasma membranes of the 3-methylcholanthrene-induced fibrosarcoma MCA-F [10].
• Injection of purified human interleukin 2 (IL-2) directly into the spleen has been shown to potentiate the effect of specific chemoimmunotherapy, using butanol-extracted tumor-specific transplantation antigen (TSTA) and cyclophosphamide (CY) in a C3H/HeJ murine methylcholanthrene-induced fibrosarcoma model [11].

Biological context of Hsp90ab1

• The common tetratricopeptide repeat acceptor site for steroid receptor-associated immunophilins and hop is located in the dimerization domain of Hsp90 [12].
• Chromosomal analysis indicated that hsp84-related sequences are on at least three different chromosomes [13].
• The steady-state levels of HSP86 and HSP84 paralleled the pattern of the expression of their respective mRNAs, suggesting that regulation at the level of translation was not a major mechanism controlling hsp90 gene expression in testicular cells [14].
• The amino acid sequences deduced from the contiguous ORF of the hsp84 and the hsp84-related cDNA coincide with the N-terminal sequence of formerly identified 84-kDa and 86-kDa tumour-specific transplantation antigens (Ullrich et al., 1986) [15].
• Hsp90 was required for signal transducers and activators of transcription 1 phosphorylation, and in its absence, Janus kinase (JAK) 1/2 were degraded by the proteosome [16].

Anatomical context of Hsp90ab1

• By contrast, the HSP84 protein was detected in the somatic cells of the testis rather than in germ cells [14].
• The biological consequences were suggested by experiments showing that T cell activation by interferon-gamma-primed macrophages and the antiviral response of interferons required Hsp90 [16].
• The interaction between Hsp90 and eNOS enhances the activation of the enzyme in cells and in intact blood vessels leading to NO production [17].
• Geldanamycin (0.1, 0.3, 1 mg kg(-1)), a specific inhibitor of Hsp-90, that inhibits endothelium-dependent relaxations of the rat aorta, mesentery and middle artery inhibits carrageenan-induced mouse paw oedema in a dose dependent manner [17].
• In various cellular models, increased levels of Hsp70 and Hsp90 promote tau solubility and tau binding to microtubules, reduce insoluble tau and cause reduced tau phosphorylation [18].

Associations of Hsp90ab1 with chemical compounds

• Comparison of the NH2-terminal and CNBr-fragment sequence data to the sequences of the yeast and Drosophila heat shock proteins (Hsp90 and Hsp83, respectively) reveals that 73 of 91 residues compared are identical [19].
• We now report that this regulation occurred with both the HSP86 and HSP84 forms of HSP90 as well as with the 94-kilodalton glucose-regulated protein [20].
• Geldanamycin treatment, which specifically inhibits Hsp90, caused a partial loss of wild-type Galpha(12) and a complete loss of the Cys-11 mutant from the lipid rafts and the appearance of a higher molecular weight form of Galpha(12) in the soluble fractions [21].
• Surprisingly, we found, using highly purified proteins, that only Hsp90 and Hsc70 are required for the activation of glucocorticoid receptors in the presence of steroids; in the absence of steroids, either p23 or molybdate are also required as reported previously [22].
• Aldosterone led to increased association of Src with HSP84 [23].

Physical interactions of Hsp90ab1

• Hsp90 is reported to bind to and stabilize Akt kinase and also to bind to DSG [24].
• Despite belonging to a class of NR not known to interact with cytosolic chaperone complexes, we have recently shown that PPARalpha interacts with heat shock protein 90 (Hsp90), although the biological consequence of this association was unknown [25].

Regulatory relationships of Hsp90ab1

• GD has been used to investigate the mechanisms by which Hsp90 regulates inflammatory cytokine production [26].

Other interactions of Hsp90ab1

• The findings presented herein suggest that HSP86 and HSP84 may have different functions [27].
• By peptide-sequencing we have identified the two heat shock proteins that bind to murine STI1 (mSTI1) as HSC 70 and HSP 84/86 [28].
• Expression of HSP32, HSP60, HSP70, HSP84, HSP86 and heat shock cognate protein (HSC)70 mRNAs was examined by in situ hybridization [29].
• Conformational activation of a basic helix-loop-helix protein (MyoD1) by the C-terminal region of murine HSP90 (HSP84) [30].
• Yet DSG did not inhibit the binding of Hsp90 to Akt kinase [24].

Analytical, diagnostic and therapeutic context of Hsp90ab1

• Immunoprecipitation analysis revealed that a 70-kDa protein coprecipitated with the HSP86/HSP84 proteins in testicular homogenates [14].
• Northern blot hybridization experiments reveal a 2.6-kb poly(A)+RNA when probed with the hsp84 clone and a 2.85-kb signal with the hsp84-related cDNA [15].
• We verified array results with RT-PCR and Northern blotting for three genes which are related to oxidative damage closely, including Hsp84, Hsp86 and YB-1 [31].
• These results suggest that Hsp90 inhibitors can effectively suppress Akt activity in animal models of human cancer at nontoxic doses, thus sensitizing tumor cells to proapoptotic stimuli [32].
• Vaccination of mice with GRP94/gp96, the endoplasmic reticulum Hsp90, elicits a variety of immune responses sufficient for tumor rejection and the suppression of metastatic tumor progression [33].

References