Disease relevance of Hspa1a

• BACKGROUND: Hspa1a and Hspa1b genes encode stress-inducible 70-kDa heat shock proteins (Hsp70) that protect cells from insults such as ischemia [1].
• We conclude that inducible HSP70.1 and HSP70.3 are required for late-phase protection against infarction following IP in mice [2].
• The findings here that VK1 and VK2 inhibit heat-shock-induced Hsp72 suggest their possible use as an adjuvant for hyperthermia in cancer therapy [3].
• The first objective was to determine whether Hsp72 is released within air spaces and whether Hsp72 levels in pulmonary edema fluid would correlate with the capacity of the alveolar epithelium to remove alveolar edema fluid in patients with ALI/ARDS [4].
• The full-length mouse Hsp72 specifically bound to P388D1 cells, but not to mastocytoma P815 cells [5].

High impact information on Hspa1a

• Hsp72 also inhibited JNK-dependent apoptosis [6].
• Hsp72 antisense oligonucleotides blocked Hsp72 production in NIH 3T3 cells in response to mild heat shock and concomitantly abolished the suppressive effect of mild heat shock on UV-induced JNK activation and apoptosis [6].
• In scrapie-infected N2a (ScN2a) cells, Hsp72 and Hsp28 were not induced by heat shock, sodium arsenite, or an amino acid analog, in contrast to uninfected control N2a cells, while other inducible Hsps were increased by these treatments [7].
• Mouse embryonic fibroblasts (MEFs) prepared from Hsp70.1/3(-/-) mice did not synthesize Hsp70.1 or Hsp70.3 after heat-induced stress [8].
• In order to determine whether such proteins specifically influence genomic instability, mice deficient for Hsp70.1 and Hsp70.3 (Hsp70.1/3(-/-) mice) were generated by gene targeting [8].

Biological context of Hspa1a

• However, these results clearly indicate that some minimal amount of Hsp70-1 and/or Hsp70-3 is required for preimplantation embryogenesis, and that increasing the demand for Hsp70s by arsenic exposure heightens this requirement [9].
• Mouse 70-kDa heat shock proteins Hsp70-1 and Hsp70-3 (Hsp70-1/3) are stress-inducible protein chaperones thought to protect embryonic cells and tissues from the effects of a wide range of environmental exposures [9].
• The transcription initiation site of the Hsc70t gene was located at ca. 600 bp upstream of the heat-inducible Hsp70.3 gene, linked head-to-head [10].
• Histology and immunohistochemistry for the inducible heat shock protein 70 (hsp70), the constitutive heat shock protein 70 (hsc70), and westem blot analysis, reverse transcriptase-polymerase chain reaction for hsp70.1 and hsp70.3 were performed just before photic injury and after 1, 4, 7, and 14 days [11].
• At the cellular level, inactivation of hsp70.1 or hsp70.3 resulted in deficient maintenance of acquired thermotolerance and increased sensitivity to heat stress-induced apoptosis [12].

Anatomical context of Hspa1a

• SEB-treated (5 or 100 microg intraperitoneally) mice revealed increased Hsp25 and Hsp72, but not Hsc73, in jejunal lymphocytes and epithelial cells [13].
• We conclude that the protective effect of Hsp72 occurs upstream of the mitochondria and not through the inhibition of the apoptosome [14].
• Of four additional, randomly chosen mouse cell lines, three show no or minimal hsp70.3 heat shock responsiveness and CpG methylation of both hsp70 genes, and two of the three lines exhibit a suboptimal hsp70.1 response to heat shock as well [15].
• By simultaneously measuring cytochrome c localization and nuclear morphology in mouse embryo fibroblasts, we have shown that Hsp72 blocks cytochrome c release from mitochondria in response to cytotoxic stress and that permeabilization of the outer mitochondrial membrane is the critical point in deciding the fate of the cell [14].
• IP significantly increased steady-state levels of HSP70.1 and HSP70.3 mRNA and expression of inducible HSP70 protein in WT myocardium [2].

Regulatory relationships of Hspa1a

• Hsp72 inhibits apoptosis upstream of the mitochondria and not through interactions with Apaf-1 [14].

Other interactions of Hspa1a

• We previously described a recombinational hotspot within the 50-kb Hsp70.3-G7 interval in the class III region of the mouse MHC [16].
• Although an attenuated increase in Hsp68 mRNA was found in E2F1 -/- mice, no changes in the proapoptotic transcripts were found after ischemia, and a mechanistic inference was not possible [17].
• Heat-treated v-fos-transformed cells displayed a decreased expression and accumulation of the major stress proteins Hsp68 (68-kDa heat-shock protein) and Hsp25 which probably resulted of a reduced accumulation of the corresponding mRNAs [18].
• A dramatical increase in Hsp72/Hsp73 expression was found at the 2-cell stage [19].
• Hsp72 did not inhibit apoptosis in mouse embryo fibroblasts once cytochrome c had been released from the mitochondria [14].

Analytical, diagnostic and therapeutic context of Hspa1a

• Southern blot analyses reveal extensive CpG methylation of a 1.2-kilobase region spanning the hsp70.1 transcription start site and hypermethylation of the adjacent hsp70.3 gene, which is presumably also inaccessible to regulatory factors [15].
• We investigated the role of inducible heat shock proteins 70.1 and 70.3 (HSP70.1 and HSP70.3, respectively) in myocardial ischemic preconditioning (IP) in mice [2].
• Apoptosis in spermatocytes was confirmed by TUNEL, and was temporally correlated with the expression of stress-inducible Hsp70-1 and Hsp70-3 proteins in spermatocytes [20].
• Hsp68 expression is analysed in various cell types and cell lines by immunoblot with antibody 8F7 and in parallel by autoradiography after metabolic labeling with [35S]methionine [21].
• In vivo binding between endogenous Hsp72 and JNK1 in NIH 3T3 cells was confirmed by co-immunoprecipitation [6].

References