Disease relevance of HSP90AB1

• Recombinant human HSP90 beta and recombinant yeast HSP90 as His6 constructs were also expressed in and purified from E. coli [1].
• The most active compounds in the ATPase assays also showed the greatest growth-inhibitory potency in HCT116 human colon cancer cells and the established molecular signature of Hsp90 inhibition, i.e., depletion of client proteins with upregulation of Hsp70 [2].
• Expression of hsp90 and cyclin D1 in human breast cancer [3].
• Shepherdin[79-83] abolished growth of AML xenograft tumors (mean of control group = 1698 mm3 and mean of treated group = 232 mm3; difference = 1466 mm3, 95% confidence interval = 505.8 to 2426; P = .008) without systemic or organ toxicity and inhibited Hsp90 function in vivo [4].
• Apoptosis, Hsp90 client protein expression, and mitochondrial dysfunction were evaluated in AML types (myeloblastic, monocytic, and chronic myelogenous leukemia in blast crisis), patient-derived blasts, and normal mononuclear cells [4].

Psychiatry related information on HSP90AB1

• The patients with 'high' levels of antibody to HSP70 showed higher initial Brief Psychiatric Rating Scale (BPRS) scores and showed greater clinical improvement than those with 'low' levels, while the patients with 'high' levels of antibody to HSP90 did not [5].

High impact information on HSP90AB1

• Heat shock protein 90 (Hsp90) is a molecular chaperone essential for activating many signaling proteins in the eukaryotic cell [6].
• Hsp90 Cochaperone Aha1 Downregulation Rescues Misfolding of CFTR in Cystic Fibrosis [7].
• In a novel in vitro system, in which human HSF1 can be activated by nonnative protein, heat, and geldanamycin, addition of Hsp90 inhibits activation [8].
• We speculate that the inhibitory effect of the unliganded steroid binding domain may be mediated by heat shock protein hsp90, which binds selectively to the unliganded receptor [9].
• These results suggest that dissociation of hsp90 and conversion to an inactive 4S intermediate could occur before the final event in ligand-mediated transactivation of gene expression [10].

Chemical compound and disease context of HSP90AB1

• Our results indicate that inhibition of the hsp90-dependent trafficking mechanism prevents aggregation of the expanded glutamine androgen receptor, thereby opening a variety of novel therapeutic approaches to these neurodegenerative disorders [11].
• The molecular chaperone hsp90 has emerged as an important therapeutic target in cancer and neurodegenerative diseases, including the polyglutamine expansion disorders, because of its ability to regulate the activity, turnover and trafficking of many proteins [11].
• To address this, we examined whether the heat shock protein 90 (Hsp90) inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), would be efficacious in inhibiting breast cancer metastasis to bone [12].
• Here, we examined the effect of the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) on doxorubicin-induced apoptosis in lymphoma [13].
• We investigated the effects of cisplatin and the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in combination in a panel of human colon adenocarcinoma cell lines that differ in their p53 and mismatch repair status [14].

Biological context of HSP90AB1

• HSP90 increases the phosphorylation of N-WASP by v-Src, leading to enhanced N-WASP-dependent actin polymerization [15].
• The spliced mRNA sequence contained a single open reading frame encoding an 84,564-dalton polypeptide showing high homology with the hsp82 to hsp90 proteins of other organisms [16].
• The evidence of p53-repressed hsp90beta gene expression in UV-irradiated cells shed light on a novel pathway of Hsp90 in the survival control of the stressed cells [17].
• PKC epsilon is a unique regulator for hsp90 beta gene in heat shock response [18].
• In order to define the mechanisms responsible for the regulated expression of a human 90-kDa heat shock protein (HSP90) gene, we have determined the complete genomic sequence of the gene encoding HSP90 beta, including 1102 base pairs upstream of the transcription initiation site [19].

Anatomical context of HSP90AB1

• These findings suggest that HSP90 induces efficient activation of N-WASP downstream of phosphorylation signal by Src family kinases and is critical for N-WASP-dependent podosome formation and neurite extension [15].
• Taxotere prevented the VEGF-induced phosphorylation of focal adhesion kinase, Akt, and endothelial nitric oxide synthase (eNOS), all of which are Hsp90 client proteins [20].
• Here we present data that pan-PKC inhibitor GF109203X, but not classic PKC inhibitor Gö6976, specifically repressed heat shock-induced accumulation of mRNA as well as promoter activity of hsp90 beta, but not hsp90 alpha, in Jurkat cells [18].
• On the other hand, the metal administration led to an increase of Hsp90 level in the cytosol, while the cytosolic levels of Hsp70 isoforms remained unaltered [21].
• A CyP4O-associated protein was isolated from rabbit reticulocyte lysate by means of an affinity resin, and was identified as hsp90 [22].

Associations of HSP90AB1 with chemical compounds

• The ability of the promoter region to respond to heat shock was examined by constructing a plasmid containing the 5' end of the HSP90 beta gene driving a neomycin phosphotransferase reporter gene [19].
• The effect of PKC-epsilon on hsp90 beta expression seems to be stimuli-specific, as phorbol myristate acetate-mediated hsp90 beta expression was PKC-epsilon-independent [18].
• Independent expression of two domains of CyP-40 permitted dissociation of N-terminal isomerase and CsA binding activity from the hsp90 binding site, which is located at the FKBP-59-like C-terminal region [23].
• Geldanamycin is an antitumor drug that binds HSP90 and induces a wide range of heat shock proteins, including HSP70s [24].
• Interaction of rat renal glucocorticoid receptor with Hsp90 and Hsp70 upon stress provoked by mercury [21].

Physical interactions of HSP90AB1

• Heat shock induced conformational change of wild type p53 and binding to hsp90 [25].
• Expression of mutant p53 prevents MDM2 from binding ARF and accumulating in the nucleolus in an hsp90-dependent fashion [26].
• Here, we ask if wheat germ lysate also contains immunophilins of the FK506-binding class (FKBPs) that bind to the hsp90 component of the chaperone complex via tetratricopeptide repeat (TPR) domains [27].
• In hypotonic cell extract (cytosol), unliganded progesterone receptor (PR) is known to form an oligomeric complex with heat shock protein 90 (hsp90), and this complex does not bind to DNA [28].
• Treatment of cells with the hsp90 inhibitor geldanamycin inactivates steroid binding activity and increases the rate of GR turnover [29].

Enzymatic interactions of HSP90AB1

• In addition, HSP90 protects phosphorylated and activated N-WASP from proteasome-dependent degradation, resulting in amplification of N-WASP-dependent actin polymerization [15].

Co-localisations of HSP90AB1

• In AD brains, levels of HSP90 were increased in both the cytosolic and membranous fractions, and HSP90 was colocalized with amyloid plaques [30].

Regulatory relationships of HSP90AB1

• Here, we show that heat shock protein 90 (HSP90) regulates N-WASP-induced actin polymerization in cooperation with phosphorylation of N-WASP [15].
• Interactions between hsp90 and non-native beta-galactosidase neither lead to refolding nor stimulate hsp70- and hdj-1-dependent refolding [31].
• In order to further elucidate the role of hsp90 in the endocrine response of cells, we have examined the effects of dexamethasone and RU38486 on the level of hsp90 mRNA in a system in which glucocorticoids down-regulate glucocorticoid receptor mRNA levels [32].
• RACK1 activity is required for the mechanism of action for the HSP90 inhibitor 17-allylaminogeldanamycin to induce HIF-1alpha degradation [33].
• HSF1 transactivation competence is repressed by an HSP90-containing multichaperone complex that interacts with trimeric factor [34].

Other interactions of HSP90AB1

• Interaction of HSP90 to N-WASP leads to activation and protection from proteasome-dependent degradation [15].
• The biological association of CyP-40 with hsp90 in many tissues may reflect a conjoint role in protein folding and trafficking [23].
• Biochemical and genetic results suggest that HSP90, through its interaction with SGT1 (SUGT1), is required for kinetochore assembly [35].
• These results suggest that the phosphorylations in the charged linker region of the HSP90 molecule modulate the formation of the functional cytosolic AhR complex [36].
• Furthermore, time-course experiments revealed that transient treatment with 17-AAG between late S and G2/M phases causes substantial delocalization of CENP-H and CENP-I, a finding that strongly suggests that HSP90 participates in kinetochore assembly in a cell cycle-dependent manner [35].

Analytical, diagnostic and therapeutic context of HSP90AB1

• The Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG), which is currently in clinical trials, is thought to exert antitumor activity by simultaneously targeting several oncogenic signaling pathways [35].
• Similar molecular alterations were induced by docetaxel plus trastuzumab combination, except for that there was a transient and complete disappearance of AR and HSP90 proteins 24 h after treatment [37].
• The HSPs have thus become targets for rational anti-cancer drug design: HSP90 inhibitors are currently showing much promise in clinical trials, whereas the increased expression of HSPs in tumors is forming the basis of chaperone-based immunotherapy [38].
• In homogenates of the same tissue samples that were used for immunohistochemistry, the PR was complexed with hsp90 [39].
• Therefore, our results indicate that the high potency of GA in cell culture and in vivo can be accounted for by its time-dependent, tight binding to Hsp90 alone [40].

References