HUMAN S-MU BINDING PROTEIN-2 BINDS TO THE DRUG RESPONSE ELEMENT AND TRANSACTIVATES THE HUMAN APOA-I PROMOTER - ROLE OF GEMFIBROZIL

Previously, we demonstrated that protein-DNA interactions at the drug response element (DRE) in the human apoA-I promoter were important for the induction of apoA-I gene expression by gemfibrozil. We now report the cloning and characterization of a DRE transactivating factor. The cloned protein is identical to the putative helicase and potential tr anscription factor human S mu binding protein-2 (HS mu BP2). It is als o related to glial factor-1 (GF1), an incomplete version of HS mu BP2 lacking the first 494 and the last 128 amino acids. Gel mobility shift assays demonstrated that HS mu BP2 binds apoA-I DRE oligomers and for ms a specific protein-DNA complex. Northern blot analysis showed that HS mu BP2 mRNA is expressed at various levels in a wide range of human tissues. Transient cotransfection experiments performed in HepG2 cell s demonstrated that overexpression of HS mu BP2 or GF1 induced apoA-I proximal promoter activity by 3-fold and that the apoA-I DRE was neces sary for transactivation. Additionally, we demonstrated that transacti vation was increased a further 2- to 3-fold by exposing the cells to g emfibrozil. Together these observations indicate that HS mu BP2 acts a s a transcription factor that regulates apoA-I gene expression in hepa toma cells and whose activity may be stimulated by gemfibrozil treatme nt.