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, interacts preferentially with the leukocyte beta7 integrin LPAM-1 (alpha4beta7), but also with L-selectin, and with VLA-4 (alpha4beta1) on myeloid cells, and serves to direct leukocytes into mucosal and inflamed tissues. Overlapping cosmid and phage lambda genomic clones were isolated, 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 transmembrane domain, cytoplasmic domain, and 3' untranslated region are encoded together on exon 5. The mucin domain contains eight repeats in total that are subject to alternative splicing. Despite the absence of a human counterpart of the third IgA-homologous domain and lack of sequence conservation of the mucin domain, the genomic organizations of the human and mouse MAdCAM-1 genes are similar. An alternatively spliced MAdCAM-1 variant was identified that lacks exon 4 encoding the mucin domain, and may mediate leukocyte adhesion 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 proximity to the ICAM-1 and ICAM-3 genes (p13.2-p13.3). PMA-inducible promotor activity was contained in a 700 base pair 5' flanking fragment conserved with the mouse MAdCAM-1 gene including tandem NF-kB sites, and an Sp1 site; and in addition multiple potential AP2, Adh1 (ETF), PEA3, and Sp1 sites. In summary, the data establish that the previously reported human MAdCAM-1 cDNA does indeed encode the human homologue of mouse MAdCAM-1, despite gross dissimilarities in the MAdCAM-1 C-terminal structures.
Leung
E
E
Department of Molecular Medicine, School of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Berg
R W
RW
Langley
R
R
Greene
J
J
Raymond
L A
LA
Augustus
M
M
Ni
J
J
Carter
K C
KC
Spurr
N
N
Choo
K H
KH
Krissansen
G W
GW
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015815:Cell Adhesion Molecules; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D003001:Cloning, Molecular; D015894:Genome, Human; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009088:Mucoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016201:Receptors, Lymphocyte Homing / Q000235:genetics
D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D016201:Receptors, Lymphocyte Homing