RETINOID-X RECEPTOR RXR-ALPHA BINDS TO AND TRANSACTIVATES THE HEPATITIS-B VIRUS ENHANCER

A retinoid X receptor (RXR) response element was located within the functionally defined hepatitis B virus (HBV) enhancer element. A short segment of the enhancer that contains this region has been shown with genetic analysis to play a key role in the regulation of enhancer function and to represent a major determinant of liver-specific activity. Both the full-length protein and the DNA-binding domain of the liver-specific receptor RXRalpha bound to the putative retinoic acid response element in the HBV enhancer. In vivo, an HBV enhancer-reporter gene construct responds to induction with retinoic acid when cotransfected with an RXRalpha expression vector. A single-base transition (G --> A) in the HBV retinoic acid response element leads to a dramatic reduction both in the in vitro binding activity of RXRalpha and the in vivo activity of the HBV enhancer. Thus, retinoic acid and the RXRalpha are implicated as being significant determinants in the liver-specific regulation of HBV gene expression and the resultant disease pathogenesis.