Disease relevance of Serpinh1

• In addition to its role as a molecular chaperone, Hsp47 synthesis always parallels that of collagen in developing tissues and various cell lines, and in collagen-related pathological conditions such as fibrosis [1].
• Structure of the gene and its retinoic acid-regulatory region for murine J6 serpin. An F9 teratocarcinoma cell retinoic acid-inducible protein [2].
• Stress conditions other than hyperthermia, including ethanol, arsenite, and hypoxia, increased J6 mRNA levels [3].
• Neither cellular proliferation (exponential growth versus plateau phase) nor the specific heat shock temperature (41.5 degrees C versus 45 degrees C) had significant effects on J6 induction by heat stress [3].
• In previous papers, we reported that the expression of Hsp47 is closely correlated with that of various types of collagen in various cell lines and also in the progression of experimental liver fibrosis [4].

High impact information on Serpinh1

• Hsp47 is a novel stress protein in the endoplasmic reticulum that binds specifically to various types of collagens and procollagens [1].
• Hsp47 is an ER-resident stress inducible glycoprotein that specifically and transiently binds to newly synthesized procollagens [5].
• When triple helix formation of type I collagen secreted from cultured cells was monitored by protease digestion, the collagens of Hsp47+/+ and Hsp47+/- cells were resistant, but those of Hsp47-/- cells were sensitive [5].
• We also show that silencing of Hsp47 in NB cells is associated with aberrant methylation of promoter CpG islands and that Hsp47 expression can be restored after treatment with 5-Aza-dC [6].
• Our studies support a role for Hsp47 in the regulation of collagen type I and IV production in NB cells and suggest that the level of collagen expression may influence NB tumor phenotype [6].

Chemical compound and disease context of Serpinh1

• B-cell epitopes were selected from the gp21 and gp46 subunits of the envelope glycoprotein of human T-cell lymphotropic virus type 1 (HTLV-1) by computer-aided analyses of protein antigenicity [7].
• In the present study the levels of Hsp47 after exposure to two chemotherapeutic agents (bleomycin and mitomycin). ionising radiation, hyperthermia and haematoporphyrin ester (HpE) mediated PDT were compared in both mouse and human fibroblast cell lines [8].

Biological context of Serpinh1

• To identify the RA response region, we have further examined the nucleotide sequence of the 1-kilobase 5'-flanking region of the J6 gene [2].
• In this study we have reported that the J6 serpin gene is 7.7 kilobases in length and consists of five exons with an additional option [2].
• The predicted reactive site (P1-P1') of this J6 protein is Arg-Ser, which is the same as that of antithrombin III [9].
• Accumulation of type IV collagen in dilated ER leads to apoptosis in Hsp47-knockout mouse embryos via induction of CHOP [10].
• Just before the death of Hsp47(-/-) embryos, DNA fragmentation typical of apoptosis was observed at 10.5 dpc together with significantly upregulated CHOP mRNA expression [10].

Anatomical context of Serpinh1

• Hsp47-null mouse embryos produce immature type I collagen and form discontinuous basement membranes [11].
• Insufficient folding of type IV collagen and formation of abnormal basement membrane-like structure in embryoid bodies derived from Hsp47-null embryonic stem cells [11].
• Heat-shocked CHO cells also accumulated transiently high levels of J6 mRNA between 2 and 7 h following 10 min at 45 degrees C. These induction kinetics are similar to those for GP50 labeling with D-[3H]mannose and to the activation of major heat shock genes, e.g., hsp70 [3].
• Similar glycosylation patterns to those discussed above were seen in colligin isolated from primary mouse embryonic parietal endoderm cells and the murine 3T3 cell line, and in SPARC secreted by bovine corneal endothelial cells [12].
• Hsp47 was also detected in tissues derived from the neural crest mesenchyme [4].

Associations of Serpinh1 with chemical compounds

• We have recently reported a protein sequence deduced from the retinoic acid (RA)-inducible mRNA J6 as a novel serine protease inhibitor (serpin) [2].
• Pulse-labeling of cells with [35S]methionine followed by treatment with puromycin and immunoprecipitation with anti-Hsp47 and anti-procollagen antibodies revealed that Hsp47 is associated with alpha 1(I) procollagen at a very early point during translocation of the nascent procollagen chains [13].
• Upon peptide binding Hsp47 has the capacity to induce the peptide backbone to fold into a polyproline type II conformation [14].
• For these studies, we employed phosphorothioate oligodeoxynucleotides directed to the first five codons of Hsp47 that straddle the predicted translation initiation site of mouse Hsp47 [13].
• Conversely, J6 mRNA was reduced by quercetin, brefeldin A, okadaic acid, uv, and hydrogen peroxide [3].

Physical interactions of Serpinh1

• Hsp47 binds to the KDEL receptor and cell surface expression is modulated by cytoplasmic and endosomal pH [15].

Other interactions of Serpinh1

• Heat shock protein 47 (Hsp47) is a procollagen/collagen-specific molecular chaperone protein derived from the serpin family of proteins and essential for the early stages of collagen biosynthesis [14].
• The BM structures stained with anti-laminin and anti-nidogen-1 antibody became disrupted in Hsp47(-/-) embryos at 10.5 dpc [10].
• One of these mRNAs, J6, encodes a approximately 40 kDa protein as assayed by hybrid selection and in vitro translation (Wang, S.-Y., LaRosa, G., and Gudas, L. J. (1985) Dev. Biol. 107, 75-86) [9].
• Association of Hsp47, Grp78, and Grp94 with procollagen supports the successive or coupled action of molecular chaperones [16].
• In cells depleted of ATP, the release of Hsp47, Grp78, and Grp94 from maturing procollagen is delayed [16].

Analytical, diagnostic and therapeutic context of Serpinh1

• Western blotting of CHO cell homogenates, using a J6 polyclonal antibody, showed a single band with a molecular weight identical to that of GP50 [3].
• Hybrid selection of J6 mRNA from CHO cells, followed by in vitro translation, produced a single band on SDS-PAGE with a molecular weight identical to that of deglycosylated GP50 [3].
• The process of endochondral bone formation was examined with regard to expression of seven heat shock proteins (Hsps): two small Hsps, the constitutive and the inducible forms of the 70 and the 90 Hsp families, the collagen chaperone Hsp47, and a cytosolic chaperone, TCP-1alpha, using immunohistochemistry [17].
• In addition, the expression of Hsp47, and collagen mRNAs were assessed by in situ hybridization using oligonucleotide probes [18].
• The distribution of procollagen, Hsp47, and CyPB to the ER and/or pre-Golgi vesicles was verified by immunofluorescence [19].

References