Differential suppression of the aryl hydrocarbon receptor nuclear translocator-dependent function by an aryl hydrocarbon receptor PAS-A-derived inhibitory molecule.

摘要: The aryl hydrocarbon receptor (AhR) heterodimerizes with the nuclear translocator (Arnt) for transcriptional regulation. We generated three N-terminal deletion constructs of human AhR 12-24 kDa in size--namely D1, D2, and D3--to suppress Arnt function. observed that all deletions interact similar affinities. which contains part PAS-A domain interacts Arnt, inhibits formation gel shift complex. D2 suppresses 3-methylcholanthrene-induced, dioxin response element (DRE)-driven luciferase activity Hep3B cells exogenous reverses this suppression. induction CYP1A1 at both message protein levels cells; however, CYP1B1 is not affected. recruitment to cyp1a1 promoter but cyp1b1 promoter, partly because AhR/Arnt heterodimer binds better DRE than DRE. Interestingly, has no effect on cobalt chloride-induced, hypoxia inducible factor-1 (HIF-1)-dependent expression vegf, aldolase c, ldh-a messages. Our data reveal flanking sequences contribute binding affinity its endogenous enhancers function HIF-1 can be differentially suppressed by inhibitory molecule.