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 inflammatio n, and its integrin counter receptor, alpha4beta1, on immune cells is responsible for targeting these immune cells to cytokine-stimulated en dothelium. In addition to its role in the immune system, VCAM-1 is als o expressed in a developmentally specific pattern on differentiating s keletal muscle, where it mediates cell-cell interactions important for myogenesis through interaction with alpha4beta1. In contrast to endot helium, there is high basal expression of VCAM-1 in skeletal muscle ce lls and the expression is not cytokine-responsive. Here, we examine th e molecular basis for these contrasting patterns of expression in musc le and endothelium, using VCAM-1 promoter constructs in a series of tr ansfection 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-kappaB binding sit es. In muscle cells, a position-specific enhancer located between bp - 21 and -5 overrides the effect of other promoter elements, resulting i n constitutive VCAM-1 expression. A nuclear protein binds the position -specific enhancer in muscle but not endothelial cells; thus the patte rn of expression of this protein could control enhancer activity.