Vascular cell adhesion molecule 1: contrasting transcriptional control mechanisms in muscle and endothelium.
Interaction between vascular cell adhesion molecule 1 (VCAM-1), which appears on the surface of endothelial cells in response to inflammation, and its integrin counter receptor, alpha 4 beta 1, on immune cells is responsible for targeting these immune cells to cytokine-stimulated endothelium. In addition to its role in the immune system, VCAM-1 is also expressed in a developmentally specific pattern on differentiating skeletal muscle, where it mediates cell-cell interactions important for myogenesis through interaction with alpha 4 beta 1. In contrast to endothelium, there is high basal expression of VCAM-1 in skeletal muscle cells and the expression is not cytokine-responsive. Here, we examine the molecular basis for these contrasting patterns of expression in muscle and endothelium, using VCAM-1 promoter constructs in a series of transfection assays. In endothelial cells, octamer binding sites act as silencers that prevent VCAM-1 expression in unstimulated cells. Tumor necrosis factor alpha overcomes the negative effects of these octamers and activates the promoter through two adjacent NF-kappa B binding sites. In muscle cells, a position-specific enhancer located between bp -21 and -5 overrides the effect of other promoter elements, resulting in constitutive VCAM-1 expression. A nuclear protein binds the position-specific enhancer in muscle but not endothelial cells; thus the pattern of expression of this protein could control enhancer activity.
Iademarco
M F
MF
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
McQuillan
J J
JJ
Dean
D C
DC
D000818:Animals; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D009928:Organ Specificity; D010957:Plasmids; D011401:Promoter Regions, Genetic; D015183:Restriction Mapping; D016385:TATA Box; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1
D015815:Cell Adhesion Molecules; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D019010:Vascular Cell Adhesion Molecule-1; D015500:Chloramphenicol O-Acetyltransferase