MOLECULAR-CLONING OF A GENE ENCODING A NEW-TYPE OF METALLOPROTEINASE-DISINTEGRIN FAMILY PROTEIN WITH THROMBOSPONDIN MOTIFS AS AN INFLAMMATION ASSOCIATED GENE

A cellular disintegrin and metalloproteinase (ADAM) is a new family of genes with structural homology to the snake venom metalloproteinases and disintegrins. We screened genes which were selectively expressed i n the cachexigenic colon 26 adenocarcinoma subline in vivo. It was fou nd that one novel cDNA clone, identified as a cachexigenic tumor selec tive gene, encodes a cysteine-rich protein which shows a sequence simi larity to that of both the snake venom metalloproteinases and thrombos pondins. We named this cDNA clone A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-1). ADAMTS1 consists of six domains , 1) a pro- and 2) a metalloproteinase, 3) a disintegrin-like, 4) a th rombospondin (TSP) homologous domain containing TSP type I motif, 5) a spacer region, and 6) COOH-terminal TSP submotifs. Unlike other ADAMs , ADAMTS-1 does not possess a transmembrane domain and is a putative s ecretory protein. Therefore, ADAMTS-1 is a new type of ADAM family pro tein with TSP type I motifs. We demonstrated that the TSP homologous d omain containing the TSP type I motif of ADAMTS-1 is functional for bi nding to heparin. ADAMTS-1 mRNA could be induced by stimulating colon 26 cells with an inflammatory cytokine, interleukin-1, in vitro. Moreo ver, intravenous administration of lipopolysaccharide in mice selectiv ely induced ADAMTS-1 mRNA in kidney and heart. These data suggest that ADAM-TS-1 may be a gene whose expression is associated with various i nflammatory processes as well as development of cancer cachexia.