ADAMTS1 Is a Unique Hypoxic Early Response Gene Expressed by Endothelial Cells

Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2009; 284(24):16325-33. DOI: 10.1074/jbc.M109.001313
Source: PubMed


ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is a member of the matrix metalloproteinase family. We have previously reported that ADAMTS1 was strongly expressed in myocardial infarction. In this study, we investigated whether hypoxia induced ADAMTS1 and investigated its regulatory mechanism. In hypoxia, the expression level of ADAMTS1 mRNA and protein rapidly increased in endothelial cells, but not in other cell types. Interestingly, the induction of ADAMTS1 by hypoxia was transient, whereas vascular endothelial growth factor induction by hypoxia in human umbilical vein endothelial cells (HUVEC) increased in a time-dependent manner. CoCl2, a transition metal that mimics hypoxia, induced ADAMTS1 in HUVEC. The phosphatidylinositol 3-kinase inhibitor LY294002 dose-dependently inhibited the increase of ADAMTS1 mRNA expression in hypoxia. We characterized the promoter region of ADAMTS1, and the secreted luciferase assay system demonstrated that hypoxia induced luciferase secretion in the culture medium 4.6-fold in HUVEC. In the promoter region of ADAMTS1, we found at least three putative hypoxia-inducible factor (HIF) binding sites, and the chromatin immunoprecipitation assay revealed HIF-1 binding to HIF binding sites in the promoter region of ADAMTS1 under hypoxia. Recombinant ADAMTS1 protein promoted the migration of HUVEC under hypoxic conditions. In summary, we found that ADAMTS1 is transiently induced by hypoxia in endothelial cells, and its transcription is mediated by HIF-1 binding. Our data indicate that ADAMTS1 is a novel acute hypoxia-inducible gene.

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Available from: Mehmet Zeynel Cilek
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    • "The secretion of ADAMTS1 to the ECM requires the excision of its pro-domain from the 87kD mature protein by furin-related endopeptidases[38]. Interestingly, ADAMTS1 can be transiently induced by hypoxia in endothelial cells, which is mediated by hypoxia-inducible factor 1 (HIF-1) binding to its promoter region[39]. Moreover, CD147 can be induced in a similar manner in various carcinoma cells[40]. "
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    • "common feature of human solid tumors and causes tumor cells to undergo adaptive changes that enable them to survive and proliferate . Hypoxia - inducible factor 1 ( HIF - 1 ) is a master regulator of hypoxic activation of genes for angiogenesis , hormone synthesis , glycolysis and cell survival ( Hatipoglu et al . , 2009 ; Torii et al . , 2009 ) . Hatipoglu et al . ( 2009 ) identified that there is Hypoxia Response Element ( HRE ) in the promoter region of the ADAMTS1 promoter . This upregulation of ADAMTS1 gene expression obtained from hepatocarcinoma cell type could be due to these HRE elements present in the promoter of ADAMTS1 gene . Apart from hypoxia , there is nothing known the regulation of human"
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