Disease relevance of Serpina1

• The wild-type alpha 1AT promoter (-554 to +44 bp) was highly expressed in rat hepatoma cells, but activity was 100-fold less in fibroblasts or cell hybrids [1].
• Protection by recombinant alpha 1-antitrypsin Ala357 Arg358 against arterial hypotension induced by factor XII fragment [2].
• Furthermore, Wistar rats pretreated with alpha 1-antitrypsin Ala357 Arg358 were partially protected from the circulatory collapse caused by the administration of beta-Factor XIIa [2].
• A liver-specific DNA-binding protein recognizes multiple nucleotide sites in regulatory regions of transthyretin, alpha 1-antitrypsin, albumin, and simian virus 40 genes [3].
• The relative strengths of three different promoters, Rous sarcoma virus long terminal repeat, alpha-myosin heavy chain, and alpha 1-antitrypsin, all fused to the luciferase reporter gene were determined [4].

High impact information on Serpina1

• The recently reported amino acid sequence of rat angiotensinogen was subjected to a computer-assisted search for homology with known sequences stored in a data bank and found to be significantly related to that of plasma alpha 1-antitrypsin, itself a member of a family that includes antithrombin III and ovalbumin [5].
• Expression of the liver-specific alpha 1-antitrypsin (alpha 1AT) gene is extinguished in hepatoma/fibroblast hybrids [1].
• We conclude that although extinction of the LF-B1 trans-activator accompanies alpha 1AT extinction in cell hybrids, it does not play a causal role in this process [1].
• Extinction of alpha 1-antitrypsin gene expression in somatic cell hybrids: evidence for multiple controls [1].
• To define the mechanism of extinction, we identified DNA sequences involved in this process by transiently transfecting mutant alpha 1AT promoters into parental and hybrid cells [1].

Chemical compound and disease context of Serpina1

• Recently we reported that the contractile agonist angiotensin II induces hypertrophy, not hyperplasia, in cultured rat aortic smooth muscle cells (Geisterfer AAT, Peach MJ, Owens GK: Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells [6].
• Our data show that alpha 1-AT treatment prevented the reduced lung compliance observed in the untreated hyperoxia-exposed neonatal rats, as well as the right ventricular hypertrophy and the associated vascular changes of medial hypertrophy of muscular arteries and muscularization of distal arteries [7].
• Regulation of the acute phase response genes alpha 1-acid glycoprotein and alpha 1-antitrypsin correlates with sensitivity to thermal injury [8].
• The effect of repeated intravenous injections of Escherichia coli endotoxin on lung structure and lung parenchymal elastin proportions was studied in rats rendered deficient in alpha 1-antitrypsin by administration of galactosamine [9].

Biological context of Serpina1

• A cDNA clone encoding rat alpha 1-antitrypsin has been isolated from a lambda gt-11 rat liver cDNA library using an antigen-overlay immunoscreening method [10].
• Surprisingly, although constitutive LF-B1 expression could activate alpha 1AT-CAT transgenes in these cells, it neither prevented nor reversed extinction of the chromosomal alpha 1AT genes [1].
• This suggested that alpha 1AT extinction in hybrids might be an indirect, lack-of-activation phenotype mediated primarily through repression of LF-B1 [1].
• Mutations in this region failed to activate alpha 1AT expression in nonhepatic cells, but mutations in the binding site for liver factor B1 (LF-B1) reduced hepatic-specific expression greater than 100-fold [1].
• Assignment of human alpha 1-antitrypsin to chromosome 14 by somatic cell hybrid analysis [11].

Anatomical context of Serpina1

• Northern blot analysis using the cDNA probe showed that rat alpha 1-antitrypsin is expressed at high levels in the liver and at low levels in the submandibular gland and the lung.(ABSTRACT TRUNCATED AT 250 WORDS)[10]
• Normal liver and differentiated hepatoma cell lines contain a nuclear factor, HNF-1, which binds functional sequences within the promoters of the alpha and beta chains of fibrinogen and alpha 1-antitrypsin [12].
• Human alpha 1-antitrypsin ( alpha-1-AT;Pi) production was analyzed in 11 primary mouse hepatoma-human lymphoid cell hybrids and in 14 secondary rat hepatoma-human fetal liver fibroblast hybrids [11].
• The in vitro transcription system is tissue-specific in that the AAT promoter is functional in nuclear extracts prepared from the liver but not from HeLa cells [13].
• Separation of hepatocytes and sinusoidal liver cells from the rat intravenously injected with 125I-labeled AAT isozymes revealed that sinusoidal cells were responsible for the plasma clearances [14].

Associations of Serpina1 with chemical compounds

• The reactive center sequence of rat alpha 1-antitrypsin is highly conserved with respect to human alpha 1-antitrypsin, both having Met-Ser at the P1 and P1' residues [10].
• DNA-binding and antisera reactivity data suggest that HNF-4 could be identical to liver factor A1 (LF-A1), a DNA-binding activity implicated in the regulation of transcription of the alpha 1-antitrypsin, apolipoprotein A1, and pyruvate kinase genes [15].
• The specificity of serpin superfamily protease inhibitors such as alpha 1-antitrypsin or C1 inhibitor is determined by the amino acid residues of the inhibitor reactive center [2].
• Transfected cells were grown in the absence and presence of human GH and dexamethasone for the Spi 2.1 gene construct [16].
• Two of the cell lines, ALB-6 and ALB-8, expressed all five liver-specific mRNAs studied, albumin, alpha-1-antitrypsin, fibrinogen, alpha-1-acid glycoprotein, and histidase [17].

Regulatory relationships of Serpina1

• Comparable levels of mRNA for alpha 1-proteinase inhibitor were found in rat lung tissue from control and experimentally inflamed animals. alpha 2-Macroglobulin mRNA could not be detected in rat lung tissue [18].

Other interactions of Serpina1

• This pattern of expression mirrors the complex pattern of expression of many genes, such as alpha-fetoprotein, alpha 1-antitrypsin, and fibrinogen, whose promoters contain HNF-1 sites [19].
• Animals mounted both positive and negative acute phase responses at all ages, but responses were blunted in young animals, reaching adult levels by days 7-19. alpha 1-Antitrypsin mRNA had no response, and Spi 2.2 mRNA had 50% the rise seen in adults on days 3 and 7 [20].
• The same result was obtained when protease inhibitors (alpha 1-antitrypsin and alpha 2-macroglobulin) were added to Kupffer cell-conditioned medium (n = 3), thus eliminating the potential effect of matrix degradation [21].
• Minimal hepatic transit times were 17, 23, and 31 min for albumin, alpha 1-antitrypsin, and transferrin, respectively [22].
• DPP-IV-positive hepatocyte-like cells also expressed other markers of hepatocytic differentiation, including albumin, transferrin, and alpha-1-antitrypsin, suggesting that the progeny of transplanted WB-F344 cells express a complete hepatocyte differentiation program [23].

Analytical, diagnostic and therapeutic context of Serpina1

• Molecular cloning and primary structure of rat alpha 1-antitrypsin [10].
• Genomic Southern blot analysis yielded a simple banding pattern, suggesting that the rat alpha 1-antitrypsin gene is single-copy [10].
• Reagents that prevent the acyl-AAT formation inhibit triacylglycerol synthesis as does the removal of AAT from the complex by immunoprecipitation [24].
• The activities of the proposed triacylglycerol synthetase complex, acyl-CoA ligase, acyl-CoA acyltransferase (AAT), monoacylglycerol acyltransferase (MGAT), and diacylglycerol acyltransferase (DGAT), coeluted upon Cibacron blue 3GA-agarose affinity chromatography of detergent-solubilized rat intestinal microsomes [24].
• Amino-terminal sequence analysis indicated that RSI and RSII are distinct, differing at the amino-terminal residues, and are products of the rat Spi-1 locus [25].

References