Disease relevance of HSP90AA2

• We previously isolated two distinct cDNA clones for HSP90 alpha from human peripheral blood lymphocytes and from HeLa cells transfected with the adenovirus E1A gene, respectively [1].
• Stably expressed Hsp90alpha short hairpin RNA also depletes Hsp90, inhibiting proliferation and sensitizing breast cancer cells to low ritonavir concentrations [2].
• All the cases including 11 ANLL, 5 ALL and 1 MDS had higher HSP90 alpha expression than the normal subjects [3].
• In this study, an Hsp90alpha fusion protein along with the enhanced green fluorescence protein (EGFP) was expressed under the control of the human cytomegalovirus immediate early promoter [4].
• Hsp90alpha was recently found on the surface and in conditioned media of HT-1080 fibrosarcoma cells [5].

High impact information on HSP90AA2

• Hsp90alpha chaperones large C-terminally extended proteolytic intermediates in the MHC class I antigen processing pathway [6].
• Inhibition of extracellular hsp90 alpha decreases both MMP2 activity and invasiveness [7].
• Upon exposure of cells to heat shock, the heavy metal cadmium, or the amino acid analogue azetidine, transcription at the hsp90alpha and hsp70 gene loci is strongly induced, and both hsp transcription sites become associated with speckles in >90% of the cells [8].
• BDGA, used to characterize the kinetics of ligand-Hsp90 interactions, was found to bind Hsp90alpha with k(off) = 2.5 x 10(-3) min(-1), t(1/2) = 4.6 h, and Ki* = 10 nM [9].
• We demonstrate that transcription of the gene encoding a 70-kDa heat shock protein (hsp70) is diminished upon heat shock in Y79 human retinoblastoma cells (which are of neuronal origin) despite both the activation of heat shock factor 1 and induced transcription of another heat shock gene, hsp90 alpha [10].

Chemical compound and disease context of HSP90AA2

• Nicotine-induced caspase-3 activation and Hsp90 alpha expression, as well as suppression of the induction by GA, were also observed in a xeroderma pigmentosum patient-derived cell line, XP2OS cells [11].
• We purified heat shock protein 90alpha (Hsp90alpha) from the membrane fraction of high glucose-treated endothelial cells (ECs) as a binding partner for a diabetes-specific phage [12].

Biological context of HSP90AA2

• We demonstrate here that nucleotide sequences that encode HSP90 alpha map to human chromosomes 1q21.2-q22, 4q35, 11p14.1-p14.2, and 14q32 [1].
• Interestingly, one of the variations observed was a missense mutation leading to the impairment of the hsp90alpha protein [13].
• A total of 18 and 11 variants were found in the HSP90-alpha and -beta genes respectively, providing an initial view of human genetic variation in these important genes [13].
• Thus, hsp90alpha can serve as a chaperone for precursors of pMHC I at an early stage in the antigen processing pathway [6].
• Although knockdown of Hsp90beta-unlike knockdown of Hsp90alpha-was sufficient to induce apoptosis, this effect was strongly increased when both Hsp90s were targeted, indicating a cooperation of both [14].

Anatomical context of HSP90AA2

• Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha [15].
• As the most remarkable finding under these conditions, an association of EGFP-Hsp90alpha with the nuclear membrane became visible [4].
• Intracellular localization of the 90 kDA heat shock protein (HSP90alpha) determined by expression of a EGFP-HSP90alpha-fusion protein in unstressed and heat stressed 3T3 cells [4].
• When expressed in a reticulocyte lysate, the full-length human HSP90 alpha formed a dimeric form [16].
• A subset of the neuronal intranuclear inclusions stained positively for the chaperones Hsp90alpha and HDJ-2, a member of the Hsp40 family [17].

Associations of HSP90AA2 with chemical compounds

• Both of these molecular chaperones displayed ATPase activity and the ability to refold heat-inactivated luciferase in a geldanamycin- and radicicol-sensitive manner, suggesting that post-translational modifications are not involved in the modulation of Hsp90alpha activity [18].
• The human double-stranded DNA-activated protein kinase phosphorylates the 90-kDa heat-shock protein, hsp90 alpha at two NH2-terminal threonine residues [15].
• We describe the 1.75 A resolution crystal structure of human Hsp90 alpha (residues 9-236) complexed with 17-desmethoxy-17-N,N-dimethylaminoethylamino-geldanamycin (17-DMAG) [19].
• We report here the structures of the water soluble 8-aryl-sulfanyl adenine class Hsp90 inhibitors, 1 (PU-H71) and 2 (PU-H64), in complex with the N-terminal domain of human Hsp90alpha [20].
• Growth factors acting via tyrosine kinase receptors induce HSP90 alpha gene expression [21].

Physical interactions of HSP90AA2

• In this study, we reported that small glutamine-rich TPR-containing protein (SGT) interacted with not only Hsp90alpha but also Hsp90beta [22].
• We identified phosphorylations of the HSP90 subunits within the AhR complex at Ser225 and Ser254 of HSP90beta and Ser230 of HSP90alpha [23].
• However, the C-terminal 326 amino acids of GRP94 failed to form a complex with HSP90 alpha [24].
• Inhibition of LRP1 binding to extracellular HSP90alpha by neutralizing antibodies or genetic silencing of the LRP1 receptor by RNAi completely nullified hypoxia-driven HK migration [25].

Regulatory relationships of HSP90AA2

• The expression of Hsp90alpha was regulated by a signal from the cytokine receptor gp130, as is Pim-1's expression [26].
• Interleukin-4 upregulates the heat shock protein Hsp90alpha and enhances transcription of a reporter gene coupled to a single heat shock element [27].

Other interactions of HSP90AA2

• The HSP90 family of heat-shock proteins (encoded by genes for HSP90 alpha and beta) constitutes one of the major groups of proteins that are synthesized at increased rates in response to heat and other forms of stress [1].
• The human recombinant Hsp90 alpha-isoform as well as bovine brain Hsp90 were purified to homogeneity [18].
• Co-immunoprecipitation with anti-Hsp90alpha antibody followed by immunoblotting with DO-1 confirmed that p53 and Hsp90alpha were interacting proteins [28].
• PRIMA-1 treatment also resulted in the translocation of Hsp90alpha to the nucleus by 8 hours [28].
• The suppression of the hsp70.1 promoter is not caused by impaired function of HSF1, since HSF1 is equally activated in all cell types and occupies another heat-inducible promoter, hsp90 alpha [29].

Analytical, diagnostic and therapeutic context of HSP90AA2

• In this study, we found in vivo and in vitro that Hsp90alpha was recruited to the GC-rich region of the 12(S)-lipoxygenase promoter through interaction with Sp1 in A431 cells by employing DNA affinity immunoprecipitation assay and chromatin immunoprecipitation assay [30].
• Quantification of the nucleocytoplasmic distribution of wild type and modified proteins using confocal microscopy: interaction between 90-kDa heat shock protein (Hsp90 alpha) and glucocorticosteroid receptor (GR) [31].
• We cloned and sequenced a chinook salmon Hsp90 cDNA; sequence analysis shows it to be Hsp90alpha [32].
• Western blot analysis of conditioned medium showed specific secretion of HSP90-alpha but not HSP90-beta [33].
• Glycerol gradient centrifugation at the physiological salt concentration as well as native PAGE analysis of rat liver cytosol revealed oligomeric forms of HSP90alpha sedimenting at 8-10S as predominant ones [34].

References