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Cell Cycle, Cell Death, and Senescence

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

¹ I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany; ² Fred Hutchinson Cancer Research Center, Seattle, Washington; ³ Division of Immunogenetics, German Cancer Research Center, Heidelberg, Germany; and ⁴ II. Department of Internal Medicine, Leopoldina Clinic, Schweinfurt, Germany

Requests for reprints: Stephan Kanzler, II. Department of Medicine, Leopoldina Clinic, Gustav-Adolf-Str. 8, 97422 Schweinfurt Germany. Phone: 49-9721-7202484; Fax: 49-9721-7202484. E-mail: skanzler{at}leopoldina.de

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 protein-1 (AP-1) site indispensable for TGF-β–mediated induction of TRAIL. Activation of this AP-1 site is mediated by a JunD·FosB heterodimer. Expression of DNSmad4, DNJunD, or DNFosB significantly impairs TGF-β–mediated activation of the TRAIL promoter. Furthermore, with tRNA interference targeting Smad4, junD, FosB, we could abolish TRAIL expression and, subsequently, TGF-β–induced TRAIL-mediated apoptosis in hepatoma cells. Our results reveal a new AP-1 site within the TRAIL promoter functionally involved in TGF-β–induced TRAIL expression and apoptosis in hepatomas and thus provide evidence for the underlying mechanism by which TGF-β might regulate cell death in liver cancer. (Mol Cancer Res 2008;6(7):1169–77)