Disease relevance of Hsc70-4

• Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease [1].
• Recently, Hsp70 was shown to inhibit alpha-synuclein toxicity in a Drosophila model of inherited PD [1].
• The set of 19 hsp70-controlled lef ORFs (HSEpiHis lef library) supports transient expression from a late viral promoter. lef-12 did not affect expression from an early baculovirus promoter [2].
• The steric accessibility of the scs region before heat shock was 3-fold higher than either flanking region (consistent with its previously documented DNase I hypersensitivity); this increased an additional 2-fold following hsp70 gene activation without a concomitant rise in the accessibility of flanking regions [3].
• Moreover, for this study, hsp70 was more efficient than the cytomegalovirus and simian virus promoters [4].

High impact information on Hsc70-4

• In agreement with previous in vitro studies, we find that the heat shock-mediated transcriptional induction of the hsp70 genes perturbs their chromatin structure, resulting in fewer protein-DNA contacts crosslinkable in vivo by formaldehyde [5].
• The level of expression of the mammalian heat shock protein 70 (HSP70) gene is elevated in several tumour cell lines, implying that a cellular function expressed in these tumour lines can stimulate HSP70 production [6].
• Drosophila Hsc70-4 is critical for neurotransmitter exocytosis in vivo [7].
• We show that hypomorphic mutations in Drosophila Hsc70-4 (Hsc4) impair nerve-evoked neurotransmitter release, but not synaptic vesicle recycling in vivo [7].
• We suggest that Hsc4 and CSP cooperatively augment the probability of release by increasing the Ca(2+) sensitivity of vesicle fusion [7].

Chemical compound and disease context of Hsc70-4

• We show that Hsp70 gene transfer to dopamine neurons by a recombinant adeno-associated virus significantly protects the mouse dopaminergic system against MPTP-induced dopamine neuron loss and the associated decline in striatal dopamine levels and tyrosine hydroxylase-positive fibers [1].
• cAMP-response element-binding protein and heat-shock protein 70 additively suppress polyglutamine-mediated toxicity in Drosophila [8].

Biological context of Hsc70-4

• The phenotypes of Rme-8 mutants bear a strong resemblance to those of Hsc70-4, suggesting that these two genes act in a common pathway [9].
• Developmental expression revealed that hsc4 transcripts are enriched in cells active in endocytosis and those undergoing rapid growth and changes in shape [10].
• The structure and expression of three of these heat-shock cognate (Hsc) genes have been studied; Hsc1 (previously described), Hsc2, and Hsc4 are dispersed on chromosome 3 at cytological loci 70C, 87D, and 88E, respectively [11].
• The Hsp70 genes contain no intervening sequences; Hsc4 contains no insertions relative to Hsp70 in the region encoding the first 101 aa [11].
• Constitutively expressed 18S ribosomal RNA genes also exhibited unrestrained superhelical tension at a level comparable with that across hsp70 [12].

Anatomical context of Hsc70-4

• Although the mutant allele was lethal, analysis of mutant clones generated by FLP/FRT recombination demonstrated that the Sevenless-mediated internalization of Boss was blocked in mutant Hsc70-4 eye disc epithelial cells [13].
• Hsp70 reduced MPTP-induced apoptosis in the substantia nigra, and unilateral protection of the dopaminergic system by Hsp70 was associated with increased amphetamine-induced turning toward the uninjected side [1].
• The stress gene assay in the reproductive organs of adult flies revealed hsp70 expression in the testis of male flies only [14].
• The Drosophila heat shock protein 70 promoter, originating from insect genes, functioned as a strong promoter in both cell lines [15].
• Heat-shock genes coding for heat-shock protein 70 (HSP70) in Drosophila melanogaster were subcloned into an SV40/plasmid recombinant capable of replication in permissive monkey COS cells [16].

Associations of Hsc70-4 with chemical compounds

• Here we tested the potential of Hsp70 (approved gene symbol HSPA1A) for gene therapy in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of idiopathic PD [1].
• As reported previously, overexpression of heat-shock protein 70 (Hsp70) rescues polyglutamine-dependent lethality [8].
• Cordycepin also reduces heat-shock protein 70 (Hsp70) protein synthesis greater than 10-fold, while having little to no effect on mRNA accumulation [17].

Physical interactions of Hsc70-4

• Indeed, biochemical and genetic data demonstrated that Rme-8 interacts specifically with Hsc70-4 via its J-domain [9].
• The Hsc70-4 mutation also interacted genetically with a dominant-negative mutant of dynamin, a gene required for the budding of clathrin-coated vesicles (CCVs) [13].

Other interactions of Hsc70-4

• We demonstrate that the functions of both Hsc3p and Hsc4p are required for proper tissue establishment and maintenance [18].
• While transcripts from Hsc4 were equally abundant in RNA isolated from embryos, larvae and adults, Hsc1 and Hsc2 transcripts were not detected in embryo and larval RNA, and are therefore at least 20 times less abundant in these stages than in adults [11].
• The protective effects of CREB and heat-shock protein 70 against polyQ are additive, suggesting that targeting multiple pathways may be effective for treatment of polyglutamine diseases [8].

Analytical, diagnostic and therapeutic context of Hsc70-4

• However, contrary to earlier in vitro evidence that histones may be absent from actively transcribed genes, we show directly, by immunoprecipitation of in vivo-crosslinked chromatin fragments, that at least histone H4 remains bound to hsp70 DNA in vivo, irrespective of its rate of transcription [5].
• In the present study we demonstrate the utility of transgenic Drosophila as an alternative animal model for evaluating hazardous effects of the effluent from the chrome plating industry and further reveal the cytoprotective role of hsp70 and its expression as an early marker in environmental risk assessment [14].
• Drosophila heat shock protein 70 promoter (hsp70), cytomegalovirus, and simian virus early promoters, controlling the luciferase gene, were transfected into the cell cultures using liposomes [4].

References