Disease relevance of ADAM12

• In conclusion, in liver cancers ADAM9 and ADAM12 expression is associated with tumor aggressiveness and progression [1].
• In vivo, the steady-state of both ADAM9 and ADAM12 mRNA levels was nearly undetectable in both normal livers and benign tumors and increased in hepatocellular carcinomas (up to 3- and 6-fold, respectively) and liver metastases from colonic carcinomas (up to 40- and 60-fold, respectively) [1].
• The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer [2].
• Here, we used human RD rhabdomyosarcoma cells, which express ADAM12 at the cell surface, in a temporal pattern [3].
• ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor [4].

Psychiatry related information on ADAM12

• ADAM 12 is a member of a family of disintegrin-containing metalloproteases that have been implicated in a variety of diseases including Alzheimer's disease, arthritis, and cancer [5].

High impact information on ADAM12

• Recent evidence implicates three ADAMs, fertilin-alpha, fertilin-beta, and meltrin-alpha, in sperm-egg fusion and myoblast fusion [6].
• We have examined the capacity of the major cytoplasmic membrane protein (MCMP) of Legionella pneumophila, a genus common antigen and member of the hsp 60 family of heat shock proteins, to induce protective immunity in a guinea pig model of Legionnaires' disease [7].
• MCMP has potential as a vaccine against Legionnaires' disease [7].
• Guinea pigs immunized with MCMP developed a strong cell-mediated immune response to the immunogen manifest by marked cutaneous delayed-type hypersensitivity [7].
• Three forms of recombinant ADAM 12 were used in these experiments: the cys-teine-rich domain made in Escherichia coli (rADAM 12-cys), the disintegrin-like and cysteine-rich domain made in insect cells (rADAM 12-DC), and full-length human ADAM 12-S tagged with green fluorescent protein made in mammalian cells (rADAM 12-GFP) [8].

Chemical compound and disease context of ADAM12

• BACKGROUND: A Disintegrin And Metalloprotease 12 (ADAM 12) is a glycoprotein synthesised by placenta and it has been shown to be a potential first-trimester maternal serum marker for Down syndrome (DS) in two small series [9].

Biological context of ADAM12

• The up-regulation of both ADAM9 and ADAM12 was correlated with an increase in matrix metalloproteinase 2 expression and activity [1].
• A disintegrin and metalloprotease 12 (ADAM12/meltrin alpha) is a key enzyme implicated in the ectodomain shedding of membrane-anchored heparin-binding epidermal growth factor (EGF)-like growth factor (proHB-EGF)-dependent epidermal growth factor receptor (EGFR) transactivation [10].
• ADAM12 is likely involved in fusion of murine mpc and human rhabdomyosarcoma cells, but it requires yet unknown molecular partners to launch myogenic cell fusion [11].
• Finally, we demonstrate that the C1 and C2 domains of PKCepsilon both contain a binding site for ADAM12 [3].
• ADAM12 and alpha9beta1 integrin are instrumental in human myogenic cell differentiation [11].

Anatomical context of ADAM12

• Northern blot analyses showed that HSCs, but not hepatocytes, expressed transcripts for ADAM9 messenger RNA (mRNA) and both the long and short forms of ADAM12 [1].
• Finally, the endogenous Dll1 present in primary mouse myoblasts undergoes cleavage in confluent, differentiating myoblast cultures, and this cleavage is decreased by ADAM12 small interfering RNAs [12].
• All three ADAMs were found to be significantly upregulated in GC compared to non-neoplastic foveolar epithelium, with ADAM12 expression being higher in intestinal- than in diffuse-type tumors [2].
• Evaluation of the fusion rate with regard to the size of myotubes showed that both ADAM12 antisense oligonucleotides and alpha9beta1 blockade inhibited more importantly formation of large (> or =5 nuclei) myotubes than that of small (2-4 nuclei) myotubes [11].
• Overexpression of ADAM12 at the cell surface of 3T3-L1 preadipocytes achieved by transient transfection or retroviral transduction led to the disappearance of the extensive network of actin stress fibers that are characteristic of these cells, and its reorganization into a cortical network located beneath the cell membrane [13].

Associations of ADAM12 with chemical compounds

• ADAM12 and integrin beta1D expressions were increased in HOCM [14].
• Involvement of the serine/threonine p70S6 kinase in TGF-beta1-induced ADAM12 expression in cultured human hepatic stellate cells [15].
• Here, we studied the role of the serine/threonine p70S6 kinase (p70S6K) in regulating TGF-beta1-induced ADAM12 expression [15].
• In untreated cells, LY294002 but not rapamycin diminished the basal ADAM12 expression related to inhibition of Akt and the glycogen synthase kinase-3 phosphorylation [15].
• We present evidence that FISH and ADAM12 mediate the neurotoxic effect of Abeta [16].
• Human heparanase, an enzyme also linked to tumorigenesis, can promote ADAM12 sheddase activity at the cell surface through cleavage of the inhibitory heparan sulfate [17].

Enzymatic interactions of ADAM12

• Because the secreted form of ADAM12 cleaves insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5, the IGF axis may play a role in preeclampsia [18].
• ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage [5].

Regulatory relationships of ADAM12

• We conclude that both ADAM12 and alpha9beta1 integrin are expressed during postnatal human myogenic differentiation and that their interaction is mainly operative in nascent myotube growth [11].
• Expression of an ADAM12 protease-deficient mutant (ADAM12DeltaMP) blocks Abeta-induced neuronal death, and expression of an N-terminal fragment of FISH reduces Abeta toxicity [16].

Other interactions of ADAM12

• Furthermore, co-immunoprecipitation and co-localization analyses of ADAM12 and PACSIN3 proteins also revealed their interaction in mammalian cells expressing both of them [10].
• Hemodynamic unloading reduced ADAM10 and ADAM12 expressions and increased integrin beta1D expression [14].
• ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling [1].
• The human protein shows homology with Xenopus ADAM13 (44%), human ADAM19 (40%), and human ADAM12 (39%) [19].
• One main transcript is visible for ADAM-12 whereas both ADAM-10 and ADAM-15 have multiple transcripts indicating possible RNA variants potentially derived from alternative splicing or alternative use of polyadenylation sites [20].
• We demonstrate the involvement of RACK1 in mediating the PKC-dependent translocation of ADAM12 to membranes of activated hepatic stellate cells [21].

Analytical, diagnostic and therapeutic context of ADAM12

• Using degenerative RT-PCR, cDNA encoding sequences for ADAM9 and ADAM12 were identified in human activated hepatic stellate cells (HSCs) [1].
• METHODS: We developed a semiautomated, time-resolved, immunofluorometric assay for the quantification of ADAM12 in serum [18].
• An ELISA was used to determine the levels of ADAM12 in maternal serum [22].
• Accordingly, both the 68-kDa mature form of ADAM12-S and the 25-kDa prodomain could be detected using domain-specific antisera in immunoprecipitation and Western blot analyses of human serum ADAM12 and purified recombinant human ADAM12 [23].
• Using immunohistochemistry, we found ADAM12 protein expression correlated with tumor stage and grade [24].

References