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Alpha 2HS-subtypes have been analysed in samples from 700 unrelated individuals from the Brescia area (Italy) by the isoelectric focusing technique and immunofixation. The observed allele frequencies were: alpha 2HS*1 = 0.7472; alpha 2HS*2 = 0.2507; alpha 2HS*V = 0.0021.
In a sample of 97 HIV-1 seropositive persons which comprised 34 patients with AIDS, 30 patients with persistent generalized lymphadenopathy or with AIDS related complex and 33 persons who were without symptoms and called "healthy", three genetic marker systems were examined: 1) GC, the group-specific component of serum which is identical with the vitamin D binding protein (DBP) of serum, 2) ORM, the acute phase protein orosomucoid = alpha-1-acid glycoprotein of serum, and 3) A2HS, the alpha-2-AS glycoprotein of serum. The distribution of the genotypes and of the alleles in the sample of AIDS patients and of HIV-1/positive persons was not different from the distribution in control groups. An association between susceptibility and/or resistance for AIDS and these genetic marker systems was not observed.
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A sample of 300 sera from unrelated individuals from Northern Japan was examined by isoelectric focusing on polyacrylamide gels. Three common types, alpha 2HS 1-1, 2-1, and 2-2 were differentiated. The frequencies of the alpha 2HS alleles in our sample were found to be: alpha 2HS1 = 0.7250 and alpha 2HS2 = 0.2750. Analysis of 16 parents with 21 children did not show deviations from the expected mode of inheritance.
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Human cortical bones were extracted with EDTA, and the residue after EDTA extraction was digested with bacterial collagenase. Ten plasma proteins were identified and quantitated in the EDTA extracts. Three of them--IgE, IgD, and alpha 1acid-glycoprotein--had not previously been described in bone or dentine. Five plasma proteins identified in collagenase digests are albumin, IgG, IgA, IgE, and alpha 1acid-glycoprotein. IgE, alpha 1acid-glycoprotein, and alpha 2HS-glycoprotein were found to be concentrated in the bone more than other plasma proteins by factors between 11 and 525. The identification of plasma proteins was facilitated by the addition of polyethylene glycol in agarose gel. The presence of plasma proteins both in EDTA extracts and in collagenase digests suggests their structural role in bone.
Two new forms of BRP-2, a previously described bone resorptive protein, were purified from ascites fluids obtained from patients with hypercalcemia and metastatic bone cancer. The apparent molecular weights of BRP-2 and of these two proteins were 52,000, 48,000, and 46,000, respectively, as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The three proteins have essentially the same amino acid compositions but differ with respect to their carbohydrate moieties. The amino-terminal amino acid sequences of the three glycoproteins were identical to each other as well as to human serum alpha 2HS-(human serum) glycoprotein. The relationship of the three forms of BRP-2 to alpha 2HS was also established immunochemically. The ascites proteins, as well as alpha 2HS, on a molar basis, were approximately one-tenth as potent as bovine parathyroid hormone fragment (1-34) in their abilities to stimulate calcium release from bone in vitro. This study describes for the first time a possible function for human serum alpha 2HS.
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The alpha 2HS glycoprotein receptor from lymphocytes transformed by Epstein--Barr Virus was isolated by affinity chromatography. The protein receptor has a monomer Mr of 48 000, which is similar to the Epstein--Barr virus-determined nuclear antigen (EBNA), and pI = 7.2. Like EBNA the 48 000 Mr component in unfractionated labelled detergent solubilised cell supernatants also binds DNA. These results may suggest some similarity between the alpha 2HS receptor and EBNA.
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Fetuin/alpha2-HS glycoprotein (alpha2-HSG) homologs have been identified in several species including rat, sheep, pig, rabbit, guinea pig, cattle, mouse and human. Multiple physiological roles for these homologs have been suggested, including ability to bind to hydroxyapatite crystals and to specifically inhibit the tyrosine kinase (TK) activity of the insulin receptor (IR). In this study we report the identification, cloning, and characterization of the mouse Ahsg gene and its function as an IR-TK inhibitor. Genomic clones derived from a mouse Svj 129 genomic library were sequenced in order to characterize the intron-exon organization of the mouse Ahsg gene, including an 875 bp subclone containing 154 bp upstream from the transcription start site, the first exon, and part of the first intron. A second genomic subclone harboring a 3.45 kb Bgl II fragment contained exons 2, 3 and 4 in addition to two adjacent elements within the first intron-a repetitive element of the B1 family (92 bp) and a 271 bp tract of (T,C)n*(A,G)n. We have mapped mouse Ahsg at 16 cM adjacent to the Diacylglycerol kinase 3 (Dagk3) gene on chromosome 16 by genotyping interspecific backcross panels between C57BL/6J and Mus spretus. The position is syntenic with human chromosome 3q27, where the human AHSG gene resides. Using recombinant mouse alpha2-HSG expressed from a recombinant baculovirus, we demonstrate that mouse alpha2-HSG inhibits insulin-stimulated IR autophosphorylation and IR-TKA in vitro. In addition, mouse alpha2-HSG (25 microg/ml) completely abolishes insulin-induced DNA synthesis in H-35 rat hepatoma cells. Based on the sequence data and functional analysis, we conclude that the mouse Ahsg gene is the true ortholog of the human AHSG gene.
The insulin-dependent tyrosine kinase activity (TKA) of the insulin receptor (IR) plays an essential role in insulin signaling. Thus, dysregulation of IR-TKA might be an important element in the states of insulin resistance. A phosphorylated rat hepatic glycoprotein (pp63) acting as an inhibitor of IR-TK has been described. In search of the human homolog of pp63, we isolated a cDNA clone from a human liver lambda gt11 cDNA library. DNA sequence analysis reveals identity with the mRNA product of a human gene AHSG encoding a serum protein, alpha 2-Heremans Scmid-glycoprotein (alpha 2HSG), with heretofore unknown physiological function. Northern blot analysis demonstrates a 1.8-kilobase mRNA in human liver and HepG2 hepatoma cells. alpha 2HSG, purified from human serum, specifically inhibits insulin-stimulated IR autophosphorylation in vitro and in vivo as well as exogenous substrate tyrosine phosphorylation. alpha 2HSG also inhibits both insulin-induced tyrosine phosphorylation of IRS-1 and the association of IRS-1 with the p85 subunit of phosphatidylinositol-3 kinase in H-35 hepatoma cells. alpha 2HSG inhibits insulin-dependent mitogenesis, but does not affect insulin-stimulated induction of the metabolic enzyme tyrosine aminotransferase. alpha 2HSG does not compete with insulin for binding to IR. Finally, the action of alpha 2HSG is specific toward the IR-TK; its effect does not extend to insulin-like growth factor-I-stimulated TKA. Our results allow us to assign a biochemical function for human alpha 2HSG, namely regulation of insulin action at the IR-TK level.
Fetuin, a major serum glycoprotein secreted by the liver, has been shown to play a role in bone development, calcium homeostasis and insulin sensitivity. In an earlier study, we demonstrated that bovine fetuin can bind to the plasma membrane of squamous and spindle-cell carcinoma cells. To test our hypothesis that fetuin plays a causal role in skin tumorigenesis, fetuin-A null and wild-type mice were challenged using a two-stage chemically-induced carcinogenesis protocol with DMBA (7,12-dimethylbenzo(a)anthracene) as the initiator, followed by twice weekly treatments with the tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate). Tumors that developed on fetuin-A null animals grew at a similar rate as those arising on their wild-type counterparts. Absence of fetuin-A did not alter tumor onset or conversion to squamous cell carcinoma, but reduced the number of tumors per mouse by 30%. This correlated with a decrease in tumor burden in fetuin-A null animals compared to wild-type weeks 18-22 from tumor onset. In addition, tumors arising on fetuin-A null mice had a diminished proliferative index with no change in cell survival or neovascularization in comparison with wild-type tumors. Our results suggest that fetuin-A contributes to early stages of skin tumorigenesis.
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