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| | Structure of ADAM proteinase. ADAM-12 is composed of a propeptide (Pro), a metalloproteinase (Metallo), a disintegrin (Dis), a cystein-rich (Cysrich) domain followed by an EGF-like (EGF), a transmembrane (TM) and a cytoplasmic domain. ADAM-12 proteinase contains in addition a sequence recognized by furin-like enzymes (FU) (Rocks et al, 2008b). |
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| Description | The open reading frame begins at the translation initiation codon ATG at nucleotide 312. Residues 1-28 encode the signal peptide. The mature human ADAM-12L contains 881 aa with an Mr of about 96,9 and that of ADAM-12S contains 718 aa with an Mr of 77,8. Five potential N-linked glycosylation sites are present. These five sites are also found at the same position in mouse ADAM-12, whereas three additional sites present in mouse are not found in human ADAM-12. The human ADAM-12 metalloproteinase domain contains the highly conserved zinc-binding motif HEXGHXXGXXHD which is regulated by a potential "cysteine switch" in the prodomain. |
| Expression | Highly expressed in placenta and in lower amounts in skeletal muscle, heart, prostate, uterus, colon, small intestine, bladder, stomach. In prostate, uterus, colon, small intestine, bladder, stomach, the source of ADAM-12 may be the smooth muscle cells. ADAM-12 is also expressed by activated hepatic stellate cells (LePabic et al, 2003). ADAM-12 is present in higher amounts in maternal serum during pregnancy (Laigaard et al, 2006). |
| Localisation | Membrane-bound for ADAM-12L, extracellular localization for ADAM-12S. |
| Function | ADAM-12 is a catalytic active protein and functions ascribed to ADAM-12 in the literature are mostly related to its catalytic activity. Indeed, ADAM-12 is able to cleave Insulin-like Growth Factor Binding Protein-3 and-5 (IGFBP-3 and IGFBP-5). The release of increasing concentrations of bioavailable IGF through IGFBP cleavage is important during pregnancy for foetal growth (Laigaard et al, 2006). ADAM-12 is also able to cleave membrane-bound Heparin-binding EGF-like Growth Factor (HB-EGF) (Asakura et al, 2002). |
| Homology | Human version of ADAM-12 shares 84% overall amino acid identity with its mouse homolog. Homology is highest in cysteine-rich, metalloproteinase, and disintegrin domains and lower in the pro- and cytoplasmic domains. Human ADAM-12 shares about 83% with the rat homolog, 68% with zebra fish ADAM-12 and 99% with chimpanzees. Human ADAM-12 shares 45% overall amino acid similarity with ADAM-8, ADAM-9 and ADAM-15. |
| Entity | Lung cancer |
| Note | ADAM-12 mRNA and protein levels are elevated in biopsies of non small cell lung cancer compared to non cancerous lung tissues (Rocks et al, 2006). |
| Prognosis | Not determined |
| Cytogenetics | Not determined |
| Hybrid/Mutated Gene | Not determined |
| Abnormal Protein | Not determined |
| Oncogenesis | Contributes to enhance proliferation of bronchial epithelial cells through enhancement of membrane-bound HB-EGF shedding and activation of downstream HB-EGF / EGFR pathway. This cleavage also protects lung epithelial cells from etoposide-induced apoptosis (Rocks et al, 2008a). |
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| Entity | Breast cancer |
| Note | Western Blots and immunoreactivity to ADAM-12 reveals that most of the malignant breast tissues exhibit ADAM-12 expression when compared to non-malignant breast lesions. |
| Prognosis | Urine of the majority of breast cancer patients is positive for ADAM-12 compared with urine from control patients in which ADAM-12 levels are significantly lower. Moreover, median levels of ADAM-12 in urine increase with disease progression (Roy et al, 2004). |
| Cytogenetics | Not determined |
| Hybrid/Mutated Gene | Not determined |
| Abnormal Protein | Not determined |
| Oncogenesis | Overexpression of ADAM-12 accelerates tumor development and increases tumor burden. ADAM-12 overexpressing tumours display lower tumor cell apoptosis and higher apoptosis rates in stromal cells (Kveiborg et al, 2005). |
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| Entity | Bladder cancer |
| Note | ADAM-12 mRNA levels are upregulated in bladder cancer as determined by microarray analysis and RT-PCR as compared to control samples. ADAM-12 protein levels correlate with tumor stage and grade. |
| Prognosis | ADAM-12 levels are upregulated in urine of patients with bladder cancer compared with urine from healthy individuals. After removal of the tumor by surgery, levels of ADAM-12 in urine decrease. ADAM-12 is therefore an interesting biomarker of bladder cancer (Frohlich et al, 2006). |
| Cytogenetics | Not determined |
| Hybrid/Mutated Gene | Not determined |
| Abnormal Protein | Not determined |
| Oncogenesis | Not determined |
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| Entity | Hepatic cancer |
| Note | Northern Blots show that ADAM-12 is expressed in human activated hepatic stellate cells. Hepatocellular carcinomas and liver metastases display higher ADAM-12 than normal liver and benign tumors. ADAM-12 expression is also correlated with tumor aggressiveness and progression (LePabic et al, Hepatology, 2003). |
| Prognosis | Not determined |
| Cytogenetics | Not determined |
| Hybrid/Mutated Gene | Not determined |
| Abnormal Protein | Not determined |
| Oncogenesis | ADAM-12 expression is induced by Transforming Growth Factor (TGF)-β in activated hepatic stellate cells through both PI3K / p70S6K and MEK / ERK pathways (LePabic et al, 2005). |
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| Entity | Glioblastoma |
| Note | Membrane-anchored ADAM-12 is overexpressed in glioblastomas compared to non-neoplastic brain tissues. In situ hybridization shows that glioblastoma cells are responsible for this gene expression (Kodama et al, 2004). |
| Prognosis | Not determined |
| Cytogenetics | Not determined |
| Hybrid/Mutated Gene | Not determined |
| Abnormal Protein | Not determined |
| Oncogenesis | There is a relation between ADAM-12 mRNA expression and proliferative activity of gliomas. This enhanced proliferation might be related to an increase of membrane-bound pro-HB-EGF shedding. |
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| Entity | Intrauterine growth |
| Note | ADAM-12 is able to cleave Insulin-like Growth Factor Binding Proteins (IGFBP) and thereby regulates the amount of free bioactive Insulin-like Growth Factor (IGF). The proposed role of ADAM-12 is the promotion of growth and development by breaking down IGFBPs, releasing IGF for uptake into cells to promote growth (Cowans et al, 2007). |
| Prognosis | In cases of poor foetal growth, Down syndrome, trisomy 18 pregnancies or in women who later develop preeclampsia, levels of ADAM-12 during early pregnancy are significantly lower than in normal pregnancies. The lower ADAM-12 levels result in less free IGF available for cell uptake and foetal growth promotion (Laigaard et al, 2005b; Laigaard et al, 2005a; Laigaard et al, 2003). |
| Cytogenetics | Not determined |
| Hybrid/Mutated Gene | Not determined |
| Abnormal Protein | Not determined |
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| Entity | Bone growth |
| Note | ADAM-12S stimulates bone growth in ADAM-12S transgenic mice by modulating chondrocyte proliferation. Interestingly, the proteinase activity of ADAM-12 is necessary for the increased growth of bone tissues since mice expressing a truncated form of ADAM-12 lacking the pro- and metalloproteinase domains did not show an alteration in bone growth (Kveiborg et al, 2006). |
| Prognosis | Not determined |
| Cytogenetics | Not determined |
| Hybrid/Mutated Gene | Not determined |
| Abnormal Protein | Not determined |
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| Entity | Adipogenesis and myogenesis |
| Note | Involvement of ADAM-12 in adipogenesis and myogenesis through the shedding of membrane-bound HB-EGF (Kurisaki et al, 2003; Gilpin et al, 1998). |
| Prognosis | Not determined |
| Cytogenetics | Not determined |
| Hybrid/Mutated Gene | Not determined |
| Abnormal Protein | Not determined |
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| A novel, secreted form of human ADAM 12 (meltrin alpha) provokes myogenesis in vivo. |
| Gilpin BJ, Loechel F, Mattei MG, Engvall E, Albrechtsen R, Wewer UM. |
| J Biol Chem. 1998 Jan 2;273(1):157-66. |
| PMID 9417060 |
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| Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. |
| Asakura M, Kitakaze M, Takashima S, Liao Y, Ishikura F, Yoshinaka T, Ohmoto H, Node K, Yoshino K, Ishiguro H, Asanuma H, Sanada S, Matsumura Y, Takeda H, Beppu S, Tada M, Hori M, Higashiyama S. |
| Nat Med. 2002 Jan;8(1):35-40. |
| PMID 11786904 |
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| Phenotypic analysis of Meltrin alpha (ADAM12)-deficient mice: involvement of Meltrin alpha in adipogenesis and myogenesis. |
| Kurisaki T, Masuda A, Sudo K, Sakagami J, Higashiyama S, Matsuda Y, Nagabukuro A, Tsuji A, Nabeshima Y, Asano M, Iwakura Y, Sehara-Fujisawa A. |
| Mol Cell Biol. 2003 Jan;23(1):55-61. |
| PMID 12482960 |
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| ADAM12: a novel first-trimester maternal serum marker for Down syndrome. |
| Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, Uldbjerg N, Albrechtsen R, Clausen HV, Ottesen B, Wewer UM. |
| Prenat Diagn. 2003 Dec 30;23(13):1086-91. |
| PMID 14691998 |
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| ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling. |
| Le Pabic H, Bonnier D, Wewer UM, Coutand A, Musso O, Baffet G, Clement B, Theret N. |
| Hepatology. 2003 May;37(5):1056-66. |
| PMID 12717386 |
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| ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor. |
| Kodama T, Ikeda E, Okada A, Ohtsuka T, Shimoda M, Shiomi T, Yoshida K, Nakada M, Ohuchi E, Okada Y. |
| Am J Pathol. 2004 Nov;165(5):1743-53. |
| PMID 15509542 |
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| ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. |
| Roy R, Wewer UM, Zurakowski D, Pories SE, Moses MA. |
| J Biol Chem. 2004 Dec 3;279(49):51323-30. |
| PMID 15381692 |
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| A role for ADAM12 in breast tumor progression and stromal cell apoptosis. |
| Kveiborg M, Frohlich C, Albrechtsen R, Tischler V, Dietrich N, Holck P, Kronqvist P, Rank F, Mercurio AM, Wewer UM. |
| Cancer Res. 2005 Jun 1;65(11):4754-61. |
| PMID 15930294 |
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| The level of ADAM12-S in maternal serum is an early first-trimester marker of fetal trisomy 18. |
| Laigaard J, Christiansen M, Frohlich C, Pedersen BN, Ottesen B, Wewer UM. |
| Prenat Diagn. 2005 Jan;25(1):45-6. |
| PMID 15662668 |
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| Reduction of the disintegrin and metalloprotease ADAM12 in preeclampsia. |
| Laigaard J, Sorensen T, Placing S, Holck P, Frohlich C, Wojdemann KR, Sundberg K, Shalmi AC, Tabor A, Norgaard-Pedersen B, Ottesen B, Christiansen M, Wewer UM. |
| Obstet Gynecol. 2005 Jul;106(1):144-9. |
| PMID 15994630 |
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| Involvement of the serine/threonine p70S6 kinase in TGF-beta1-induced ADAM12 expression in cultured human hepatic stellate cells. |
| Le Pabic H, L'Helgoualc'h A, Coutant A, Wewer UM, Baffet G, Clement B, Theret N. |
| J Hepatol. 2005 Dec;43(6):1038-44. |
| PMID 16139919 |
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| Molecular profiling of ADAM12 in human bladder cancer. |
| Frohlich C, Albrechtsen R, Dyrskjot L, Rudkjaer L, Orntoft TF, Wewer UM. |
| Clin Cancer Res. 2006 Dec 15;12(24):7359-68. |
| PMID 17189408 |
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| ADAM12-S stimulates bone growth in transgenic mice by modulating chondrocyte proliferation and maturation. |
| Kveiborg M, Albrechtsen R, Rudkjaer L, Wen G, Damgaard-Pedersen K, Wewer UM. |
| J Bone Miner Res. 2006 Aug;21(8):1288-96. |
| PMID 16869727 |
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| ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome. |
| Laigaard J, Spencer K, Christiansen M, Cowans NJ, Larsen SO, Pedersen BN, Wewer UM. |
| Prenat Diagn. 2006 Oct;26(10):973-9. |
| PMID 16892462 |
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| Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC). |
| Rocks N, Paulissen G, Quesada CF, Polette M, Gueders M, Munaut C, Foidart JM, Noel A, Birembaut P, Cataldo D. |
| Br J Cancer. 2006 Mar 13;94(5):724-30. |
| PMID 16495931 |
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| First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system. |
| Cowans NJ, Spencer K. |
| Prenat Diagn. 2007 Mar;27(3):264-71. |
| PMID 17278174 |
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| Breast cancer-associated mutations in metalloprotease disintegrin ADAM12 interfere with the intracellular trafficking and processing of the protein. |
| Dyczynska E, Syta E, Sun D, Zolkiewska A. |
| Int J Cancer. 2008 Jun 1;122(11):2634-40. |
| PMID 18241035 |
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| The metalloproteinase ADAM-12 regulates bronchial epithelial cell proliferation and apoptosis. |
| Rocks N, Estrella C, Paulissen G, Quesada Calvo F, Gilles C, Gueders M, Crahay C, Foidart JM, Gosset P, Noel A, Cataldo D. |
| Cell Prolif. 2008;in press. |
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| Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. |
| Rocks N, Paulissen G, El Hour M, Quesada F, Crahay C, Gueders M, Foidart JM, Noel A, Cataldo D. |
| Biochimie. 2008 Feb;90(2):369-79 (REVIEW). |
| PMID 17920749 |
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