Expression of the E2F1 transcription factor overcomes type β transforming growth factor-mediated growth suppression

Inhibition of cell growth by type β transforming growth factor (TGF-β) occurs in mid-G₁ and is associated with decreased G₁ cyclin-dependent kinase activity and maintenance of the retinoblastoma tumor suppressor protein Rb in an underphosphorylated, growth-suppressive state. A variety of recent experiments suggest that a functional target of Rb is the E2F transcription factor. In addition, the growth-suppressive effects of TGF-β can be overcome by expression of viral oncogene products that dissociate E2F from Rb and Rb-related polypeptides. These results suggest the possibility that control of E2F may be a downstream event of TGF-β action. Consistent with that possibility is the observation that E2FI RNA levels are drastically reduced in TGF-β-treated cells. We have also used a recombinant adenovirus containing the human E2F1 gene to overexpress the E2F1 product in mink lung epithelial cells that were growth arrested with TGF-β. We find that overexpression of E2F1 can overcome the TGF-β-mediated effect as measured by the activation of cellular DNA synthesis. These results suggest that a likely downstream target for the cyclin-dependent kinases, which are controlled by TGF-β, is the activation of E2F.