Akt/PKB is a serine–threonine kinase that plays a critical role in cell survival signaling by phosphorylating and inactivating components of the cell death machinery. Akt has been shown to phosphorylate a subfamily of forkhead transcription factors and prevent their nuclear localization, leading to repression of genes involved in apoptosis, such as Fas ligand. Other genes involved in forkhead-mediated apoptosis have yet to be identified. Using bioinformatics approaches, we have identified genes containing forkhead factor binding sites in their promoter sequences. One gene identified by this search is that coding transforming growth factor βII (TGF-βII). We show that activated Akt can downregulate TGF-βII promoter activity and that this repression is mediated by the three forkhead factor binding sites present in its promoter region. TGF-βII (but not TGF-βI) messenger RNA levels are significantly downregulated in pancreatic and breast cancer cell lines expressing activated Akt (through either gene amplification or inactivation of the PTEN/MMAC1 tumor suppressor gene). Tumor cell lines expressing activated Akt and an intact TGF-βII signaling pathway are responsive to TGF-β-mediated growth inhibition. Our studies demonstrate that repression of TGF-βII promoter in tumors expressing activated Akt is a new mechanism to abrogate the growth inhibition or apoptotic effects (or both) of TGF-β.