HETERODIMERIC RETINOIC ACID RECEPTOR-BETA AND RETINOID-X RECEPTOR-ALPHA COMPLEXES STIMULATE EXPRESSION OF THE INTERCELLULAR-ADHESION MOLECULE-1 GENE

Human intercellular adhesion molecule-1 (ICAM-1), a specific ligand fo r the leukocyte-function associated antigen-1 and for Mac-1, plays an important role in immune responses. ICAM-1 expression is regulated by various proinflammatory cytokines, phorbol myristate acetate, and reti noic acid. In this study, we investigated the mechanisms of transcript ional control involved in the stimulation of ICAM-1 gene expression by retinoic acid in Cos-l cells. Deletion mutant analysis provided evide nce that a region located between -393 and -176 from the translational start site is critical to retinoic acid stimulation of luciferase act ivity. This region harbors the consensus sequence for a retinoic acid- responsive element (RARE) 5'-GGGTCATCGCCCTGCCA-3'. The Smal(-270)/Smal (-178) fragment containing this element conferred appropriate retinoi c acid responsiveness to an enhancerless SV40 promoter. Cotransfection of expression vectors encoding the retinoic acid receptor alpha, beta , or gamma and retinoid X receptor alpha with reporter plasmids harbor ing the putative RARE demonstrated that the ICAM-1 gene is regulated b y retinoic acid in a retinoic acid receptor beta/retinoid X receptor a lpha-dependent fashion. Electrophoretic mobility shift assays showed t hat ICAM-1 and ADH3 RARE, a well-characterized RARE, display the same band shift pattern, bind retinoic acid receptor beta and retinoid X re ceptor alpha, and are mutually competitive.