Transforming Growth Factor-β–Mediated Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Expression and Apoptosis in Hepatoma Cells Requires Functional Cooperation between Smad Proteins and Activator Protein-1

Abstract Transforming growth factor-β (TGF-β) has been shown to induce apoptotic cell death in normal and transformed hepatocytes. We recently identified tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as an important mediator of TGF-β–induced apoptosis in hepatoma cells. In this study, we have further explored the mechanism by which TGF-β up-regulates TRAIL expression. The 5′-flanking region of the TRAIL gene was isolated and characterized. Deletion mutants of the 5′-untranslated region of the TRAIL gene revealed a region comprising nucleotides −1950 to −1100 responsible for TRAIL induction following treatment with TGF-β. Within this region, we have identified an activator …