GENOMIC ORGANIZATION, CHROMOSOMAL MAPPING, AND ANALYSIS OF THE 5'-PROMOTER REGION OF THE HUMAN MADCAM-1 GENE

MAdCAM-1, the endothelial addressin cell adhesion molecule-1, interact s preferentially with the leukocyte beta 7 integrin LPAM-1 (alpha 4 be ta 7), but also with L-selectin, and with VLA-4 (alpha 4 beta 1) on my eloid cells, and serves to direct leukocytes into mucosal and inflamed tissues. Overlapping cosmid and phage lambda genomic clones were isol ated, revealing that the human MAdCAM-1 gene contains five exons where the signal peptide, two Ig domains, and mucin domain are each encoded by separate exons. The trans membrane domain, cytoplasmic domain, and 3' untranslated region are encoded together on exon 5. The mucin doma in contains eight repeats in total that are subject to alternative spl icing. Despite the absence of a human counterpart of the third IgA-hom ologous domain and lack of sequence conservation of the mucin domain, the genomic organizations of the human and mouse MAdCAM-1 genes are si milar. An alternatively spliced MAdCAM-1 variant was identified that l acks exon 4 encoding the mucin domain, and may mediate leukocyte adhes ion to LPAM-1 without adhesion to the alternate receptor, L-selectin. The MAdCAM-1 gene was located at p13.3 on chromosome 19, in close prox imity to the ICAM-1 and ICAM-3 genes (p13.2-p13.3). PMA-inducible prom otor activity was contained in a 700 base pair 5' flanking fragment co nserved with the mouse MAdCAM-1 gene including tandem NF-kappa B sites , and an Sp1 site. and in addition multiple potential AP2, Adh1 (ETF), PEA3, and Sp1 sites. In summary, the data establish that the previous ly reported human MAdCAM-1 cDNA does indeed encode the human homologue of mouse MAdCAM-1, despite gross dissimilarities in the MAdCAM-1 C-te rminal structures.