Disease relevance of HSPA1A

• Treatment of human K562 erythroleukemia cells with the antiproliferative prostaglandin A1 results in the elevated transcription of two heat shock genes, HSP70 and HSP90 [1].
• Here we show that constitutive overexpression of the major inducible heat shock protein, hsp70, in transfected human cells reduces the extent of HSF activation after a heat stress [2].
• This demonstrates that the promoter of this human hsp70 gene interacts with at least two positive transcriptional activators, CTF, which is required for CCAAT-box-dependent transcription as in other promoters such as those of globin and herpes simplex virus thymidine kinase genes, and HSTF, which is involved in heat inducibility [3].
• Western blotting analysis showed that treatment of K562 cells with HA tetrasaccharides up-regulated Hsp72 expression after exposure to hyperthermia [4].
• Induction of Hsp70 by ALLN was dose-dependent and not related to cell toxicity [5].

Psychiatry related information on HSPA1A

• Polypeptides belonging to the Hsp70 major stress protein family and to the NF-kB/Rel multi-functional regulatory complex are known to be involved in cellular defense mechanisms [6].
• However, large individual differences were observed as 3 of the 6 subjects had a marked increase in the release of Hsp72, whereas exercise had little effect on the cerebral Hsp72 balance in the remaining 3 subjects [7].
• In an investigation of heat shock proteins (HSPs) in the brains of Alzheimer's disease (AD) patients and cognitively intact control subjects, we found that 2 HSPs, termed "HSP72" and "GRP78," underwent major changes in expression in AD [8].
• Therefore, we purified a preparation of HSP70/HSC70 from bovine muscle and used it in a model of Huntington's disease [9].
• Baseline physical activity and 6-min walk distance correlated negatively with circulating IL-6 (p<0.05); except for a negative correlation between TGF-beta and Hsp70 37 degrees C L (p<0.05), no significant relationships were found between cytokines and Hsp70 [10].

High impact information on HSPA1A

• Genetic and biochemical analysis shows that several distinct chaperone systems, including Hsp70 and the cylindrical chaperonins, assist the folding of proteins upon translation in the cytosol of both prokaryotic and eukaryotic cells [11].
• Whereas the main role of the HSP70/HSP40 chaperone system is to minimize aggregation of newly synthesized proteins, the HSP60 chaperones also facilitate the actual folding process by providing a secluded environment for individual folding molecules and may also promote the unfolding and refolding of misfolded intermediates [12].
• We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5 [13].
• While both folding and degradation of VHL require Hsp70, the chaperonin TRiC is essential for folding but is dispensable for degradation [14].
• The TPR1 domain of Hop specifically recognizes the C-terminal heptapeptide of Hsp70 while the TPR2A domain binds the C-terminal pentapeptide of Hsp90 [15].

Chemical compound and disease context of HSPA1A

• Ectopic expression of Hsp70 confers resistance and silencing its expression sensitizes human colon cancer cells to curcumin-induced apoptosis [16].
• Transactivation of hsp70-1/2 in geldanamycin-treated human non-small cell lung cancer H460 cells: involvement of intracellular calcium and protein kinase C [17].
• Pretreatment of CDDP-sensitive A2780 cells with N-acetyl-L-cysteine, a precursor of GSH, effectively enhanced induction of the Hsp72 mRNA by the mild heat stress [18].
• SB203580 and dominant-negative JNK suppress hsp70 promoter-driven reporter gene expression selectively at 45 degrees C but not at 42 degrees C heat stress, suggesting that JNK would be preferentially associated with the protective heat shock response against severe heat stress [19].
• Preincubation of heated cells with quercetin inhibited strong Hsp72 expression observed after hyperthermia and changed the intracellular Hsp72 distribution [20].

Biological context of HSPA1A

• Phylogenetic analysis reveals that gene conversion has homogenized the entire coding regions of HSPA1A/B and several fragments of HSPA1L [21].
• Upregulation of a group of heat shock proteins (HSPA1A, HSPA2 and HSPA8) in chondrons was validated by real time reverse transcription polymerase chain reaction (RT-PCR) [22].
• The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression [23].
• In summary, these data suggest that induction of hsp70 expression in rheumatoid synovial tissue is based on transcriptional activation of HSF1 due to the presence of proinflammatory cytokines (and possibly also shear stress) [24].
• Activation of PKC can cause phosphorylation of HSF1, which leads to an enhanced but transient increase in HSP-70 production [25].

Anatomical context of HSPA1A

• We identified the molecular chaperone Hsp70 as an interacting partner of FANCC in lymphoblasts and HeLa cells using 'pull-down' and co-immunoprecipitation experiments [26].
• To study further the functional significance of Ku/CHBF in the cellular response to heat shock, we established rodent cell lines that stably and constitutively overexpressed one or both subunits of the human Ku protein, and examined the thermal induction of hsp70 and other heat shock proteins in these Ku-overexpressing ing cells [27].
• Here we investigated the mechanism of Hsp72-mediated protection from tumor necrosis factor (TNF)-induced apoptosis of primary culture of IMR90 human fibroblasts [28].
• Hemin-induced transcriptional activation of the HSP70 gene during erythroid maturation in K562 cells is due to a heat shock factor-mediated stress response [29].
• We observed that N-acetyl-leucyl-leucyl-norleucinal (ALLN), a synthetic aldehydic tripeptide that inhibits proteasomes, markedly induced Hsp70 levels (up to 30-fold above base line in HepG2 cells and human endothelial cells) [5].

Associations of HSPA1A with chemical compounds

• Moreover, CHIP enhanced Parkin-mediated in vitro ubiquitination of Pael-R in the absence of Hsp70 [30].
• L-glutamine potentiation of Hsp72 is associated with increased epithelial resistance to apoptotic injury [31].
• HSF activation in response to treatment with sodium arsenite or the proline analog azetidine was also depressed in hsp70-expressing cells relative to that in the nontransfected control cells [2].
• Quercetin was found to inhibit hsp70 synthesis for a period of 3-6 h after PGA1 treatment [32].
• Because MAP/AbeAdo caused also an intracelluar accumulation of putrescine, we tested the effect of exogenous putrescine, which was found to stabilize the mRNAs for hsp70 and c-jun [33].

Physical interactions of HSPA1A

• Inhibition of HSP70 expression by calcium ionophore A23187 in human cells. An effect independent of the acquisition of DNA-binding activity by the heat shock transcription factor [34].
• HspBP1 prevented ATP binding to Hsp70, and therefore this is the likely mechanism of inhibition [35].
• To further elucidate the role of the association of Hsp70 with the NQO1*1 protein, site-directed mutagenesis was used to modify a proposed Hsp70 binding site near the N terminus of the NQO1 protein [36].
• Here, we demonstrate that, during the priming step, ATP-bound hsp70 is converted to GR-bound hsp70 that is approximately 1/3 in the ADP- and approximately 2/3 in the ATP-dependent conformation [37].
• After translocation, p53 is freed from Hsp proteins for binding to DNA where Hsp70 and Hsp90 are no longer able to form a nuclear complex probably rendering Hsp's labile to proteolysis [38].

Enzymatic interactions of HSPA1A

• An increase in the intracellular Ca2+ concentration ([Ca2+]i), externalization of Fas, and decrease in Hsp70 and phosphorylated HSF1 were observed following the combined treatment [39].
• Thus, in erythroid precursors undergoing terminal differentiation, Hsp70 prevents active caspase-3 from cleaving GATA-1 and inducing apoptosis [40].

Co-localisations of HSPA1A

• After insulin treatment, Hsp70 was mostly colocalized to the plasma membrane with dystrophin [41].
• Hsp70 also colocalizes with RNA polymerase I, both being restricted to the DFC [42].
• At the onset of caspase activation, Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation [40].

Regulatory relationships of HSPA1A

• The DNA-binding activity of the human heat shock transcription factor is regulated in vivo by hsp70 [2].
• Hsp72 temporarily blocked apoptosis in response to TNF and permanently protected cells from heat shock [28].
• This effect was titratable, and higher levels of wild-type but not a mutant form of Bag1 further inhibited Hsp70 refolding by up to a factor of 5 [43].
• Expression of a dominant-negative mutant of JNK1 also suppressed glucose deprivation-induced JNK1 activation as well as HSP70 gene expression [44].
• These data indicate that we have identified a novel Hsp70-interacting protein that inhibits Hsp70 chaperone activity [35].

Other interactions of HSPA1A

• Overexpression of Hsc70, a constitutive homolog of Hsp70, prevented loss of cap-initiation complexes and maintained eIF4G solubility [45].
• Here, we show that CHIP, Hsp70, Parkin, and Pael-R formed a complex in vitro and in vivo [30].
• In contrast, nonsteroidal antiinflammatory drugs triggered only an incomplete heat shock response, with HSF1 activation but not hsp70 induction, whereas steroids and immunosuppressive drugs did not affect the heat shock response at all [24].
• Expression of HSP-70, HSF1, and HSF2 genes and protein were determined [25].
• Similar to the action of the GrpE protein on bacterial Hsp70, BAG-1 accelerates the release of ADP from Hsc70 [46].

Analytical, diagnostic and therapeutic context of HSPA1A

• Distribution of HSPA1A G(190)C was similar in the preeclamptic and control group [47].
• The PMA-induced increase in HSP-72 protein peaked 8 h after treatment with PMA and returned to baseline levels at 72 h [25].
• Camptothecin-induced apoptosis was monitored using caspase-3 and poly (ADP-ribose) polymerase [PARP]-specific antibodies and DNA Elisa +/- Hsp72 siRNA [31].
• Heat shock protein 72 (Hsp72) gene expression was determined by Northern blotting and luciferase assays [31].
• Both hemin and heat shock treatments resulted in equivalent levels of HSF-HSE complexes as analyzed in vitro by gel mobility shift assay, yet transcription of the hsp70 gene was stimulated much less by hemin-induced HSF than by heat shock-induced HSF [48].

References