Disease relevance of A2m

• Direct injection and expression in vivo of full-length cDNA of the cardiac isoform of alpha-2 macroglobulin induces cardiac hypertrophy in the rat heart [1].
• No association of three polymorphisms in the alpha-2-macroglobulin and lipoprotein related receptor genes with multiple sclerosis [2].
• Acute-phase reaction induces a specific complex between hepatic nuclear proteins and the interleukin 6 response element of the rat alpha 2-macroglobulin gene [3].
• Within the granulomas, alpha 2M protein was present in numerous spindle-shaped cells and was diffusely distributed in the extra-cellular matrix [4].
• The significance of the present study is that alpha 2M is produced locally at sites of inflammation and liver fibrosis, without measurable increase of serum levels of alpha 2M [4].

Psychiatry related information on A2m

• Results of this study indicate that the accumulation and activation of alpha 2M with inflammatory neuropathologies such as Alzheimer's disease can inhibit synaptic plasticity, which might partly account for the memory deficits seen in these patients [5].

High impact information on A2m

• The endocytic marker alpha 2 macroglobulin-gold entered the structure at 37 degrees C, but not at 20 degrees C. With prolonged chase, most of the marker was transported from the structure into lysosomes [6].
• Transglutaminase is essential in receptor-mediated endocytosis of alpha 2-macroglobulin and polypeptide hormones [7].
• The aim of this study was to examine the regulation of the alpha 2-macroglobulin gene during liver regeneration and molecular mechanisms that influence its expression [8].
• Conversely, the endocytosis and degradation of activated alpha 2-macroglobulin, a known ligand of the clathrin-dependent pathway, is not affected [9].
• Alpha 2-macroglobulin gene expression during rat development studied by in situ hybridization [10].

Chemical compound and disease context of A2m

• The purpose of this investigation was to characterize the reaction of alpha 2-antiplasmin (alpha 2AP) and alpha 2-macroglobulin (alpha 2M) with human plasmin bound to rat C6 glioma cells and human umbilical vein endothelial cells (HUVECs) [11].
• Monodansylcadaverine, an inhibitor of alpha 2-macroglobulin, epidermal growth factor, vesicular stomatitis virus, and T3 uptake in fibroblasts, blocked virtually all of the cellular uptake of T3, with a half-maximal concentration of 29 microM [12].
• The LRP is a multi-functional receptor which is shared by a variety of ligands, including alpha 2-macroglobulin, apoprotein E-enriched beta-very-low-density lipoprotein, t-PA and Pseudomonas exotoxin A [13].
• On days 2, 8 and 14 after induction of colitis with trinitrobenzenesulphonic acid in ethanol (TNBS-E), plasma endotoxin, immunoglobulin (Ig) G and IgM endotoxin-core antibody (EndoCAb), tumour necrosis factor (TNF), interleukin (IL) 6 and alpha 2-macroglobulin (alpha 2M) concentrations and colon macroscopic inflammation score were determined [14].
• In contrast, injection of 0.25 microgram LPS before induction of nephritis with 10 mg anti-GBM antibody, in rats with raised alpha 2-M, caused severe albuminuria (115 +/- 23 mg/24 h) compared with rats having normal levels of alpha 2-M (72 +/- 15 mg/24 h, P < 0.05) [15].

Biological context of A2m

• Although the amino acid sequences of rat and human alpha 2-macroglobulin share 73% identity, two small divergent areas of 17 and 38 residues were found, corresponding to 29 and 11% identity, respectively [16].
• DNA sequence analysis revealed a homology of about 80% to human alpha 2M [17].
• Six alpha 2-macroglobulin cDNA clones were isolated from two liver cDNA libraries produced from rats undergoing acute inflammation [16].
• A 5.6 kb Sal I - Xba I fragment containing the first 4 exons of the alpha 2-macroglobulin gene and 1.3 kb of its 5'-flanking region was sequenced [18].
• A glucocorticoid response element (GRE), a conserved consensus sequence for a potential glucocorticoid receptor DNA binding site, was found by computer search in the promoter-proximal 5'-flanking region of the alpha 2-macroglobulin gene [19].

Anatomical context of A2m

• Very high concentrations of alpha 2-macroglobulin mRNA originating from both start sites were also found in the uterus but not in the liver of pregnant females [19].
• In addition, alpha 2-macroglobulin mRNA was detected in brain, spinal cord and eye [10].
• It was inhibited by the variant alpha 1-antitrypsin Pittsburgh (Met358 to Arg358; K0.5 = 100 nM) but not by other related proteins normally co-secreted with albumin from hepatocytes, namely alpha 1-antitrypsin M, alpha 2-macroglobulin, or antithrombin III [20].
• Insulin stimulates receptor-mediated uptake of apoE-enriched lipoproteins and activated alpha 2-macroglobulin in adipocytes [21].
• Native and activated forms of alpha 2-macroglobulin increase expression of platelet-derived growth factor alpha-receptor in vascular smooth muscle cells. Evidence for autocrine transforming growth factor-beta activity [22].

Associations of A2m with chemical compounds

• It contains a typical internal thiol ester region and 25 cysteine residues which are conserved between rat and human alpha 2-macroglobulin [16].
• alpha 2-Macroglobulin exposure reduces calcium responses to N-methyl-D-aspartate via low density lipoprotein receptor-related protein in cultured hippocampal neurons [23].
• Poly(A)+ RNA enriched in alpha 2-macroglobulin (alpha 2M) mRNA isolated from livers of rats 18 h after injection of turpentine was used for the synthesis of double-stranded cDNA [17].
• DNA sequences containing the 5'-flanking region of the rat alpha 2-macroglobulin gene were linked to the gene coding for the bacterial chloramphenicol acetyltransferase and introduced into Hep G2 cells [18].
• Clustering and internalization of rhodamine-labeled alpha 2-macroglobulin (R alpha 2 M) in normal rat kidney (NRK) cells is inhibited by a wide spectrum of compounds that inhibit transglutaminases, including that from NRK cells [24].

Physical interactions of A2m

• In summary, results demonstrated that alpha 2M-MA enhanced TGF-beta 1-induced growth responses and that this effect was dependent on alpha 2M-MA binding to alpha 2M receptor/LRP [25].
• The increase in the binding of alpha 2-macroglobulin-protease complex parallelled an increase in the incorporation of glucosamine, although the latter did not increase to the same extent [26].

Regulatory relationships of A2m

• Moreover, proteolytic enzymes may accelerate the removal of TGF-beta 1 from renal tissue via a protease-induced activation of alpha 2-macroglobulin (alpha 2M) [27].
• The receptor-mediated endocytosis of alpha 2-macroglobulin can be inhibited by a diverse group of chemical compounds all of which share the property of being inhibitors of one form of cellular transglutaminase [7].
• However, dexamethasone at 10(-7)-10(-5) M stimulated alpha 2-macroglobulin secretion by Sertoli cells dose-dependently while the addition of interleukin-6 had no synergistic effect on dexamethasone-stimulated alpha 2-macroglobulin secretion [28].
• In this regard, the effects of transforming growth factor-alpha on cholinergic cells can be blocked with immunoneutralizing antibodies raised against alpha 2-macroglobulin [29].
• Monoamine-activated alpha-2-macroglobulin (alpha 2M) has been shown to decrease the dopamine concentrations in rat caudate putamen (CP) in vivo as well as inhibit choline acetyltransferase activities in the culture of basal forebrain neurons [30].

Other interactions of A2m

• Deletion analyses have shown that the sequences between -852 and -777 as well as between -404 and -165 relative to the cap site, contain regulatory elements involved in the interleukin-6 dependent induction of the alpha 2-macroglobulin gene [18].
• These findings show for the first time that Stat3 is involved in associating with the IL-6 responsive elements of fibrinogen gamma chain, a class II acute phase gene other than alpha 2-macroglobulin [31].
• Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator [32].
• We have identified an IL-6 responsive cis-acting element (IL-6RE) of gene encoding a typical APP, rat alpha 2-macroglobulin (alpha 2M) [33].
• Thus, the initial induction of the alpha 2M gene by PRL in differentiated rat granulosa cells involves, at least in part, the activation (tyrosine phosphorylation?) of Stat 5 [34].

Analytical, diagnostic and therapeutic context of A2m

• Using an in vitro translation system coupled with solid-phase radioimmunoassay, alpha 2M mRNA activity was found to rise to a maximum level in 16-24 h after turpentine injection [35].
• Molecular cloning of DNA complementary to rat alpha 2-macroglobulin mRNA [35].
• Sequence analysis of the putative regulatory region of rat alpha 2-macroglobulin gene [36].
• These preliminary results suggest that sterically favourable molecules which can complete the inhibiton of alpha 2-macroglobulin bound proteinases should contribute to the effective specific chemotherapy of the disease [37].
• To analyze the cellular signaling events stimulated by PRL, transient transfections of granulosa cells and electrophoretic mobility shift assays were done using the IL-6 response element (IL-6RE) of the alpha 2M promoter [34].

References