EXPRESSION OF THE E2F1 TRANSCRIPTION FACTOR OVERCOMES TYPE-BETA TRANSFORMING GROWTH FACTOR-MEDIATED GROWTH SUPPRESSION

Inhibition of cell growth by type beta transforming growth factor (TGF -beta) occurs in mid-G(1) and is associated with decreased G(1) cyclin -dependent kinase activity and maintenance of the retinoblastoma tumor suppressor protein Rb in an underphosphorylated, growth-suppressive s tate, A variety of recent experiments suggest that a functional target of Rb is the E2F transcription factor. In addition, the growth-suppre ssive effects of TGP-beta can be overcome by expression of viral oncog ene products that dissociate E2F from Rb and Rb-related polypeptides. These results suggest the possibility that control of E2F may be a dow nstream event of TGF-beta action, Consistent with that possibility is the observation that E2F1 RNA levels are drastically reduced in TGF-be ta-treated cells. We have also used a recombinant adenovirus containin g the human E2F1 gene to overexpress the E2F1 product in mink lung epi thelial cells that were growth arrested with TGF-beta, We find that ov erexpression of E2F1 can overcome the TGF-beta-mediated effect as meas ured by the activation of cellular DNA synthesis, These results sugges t that a likely downstream target for the cyclin-dependent kinases, wh ich are controlled by TGF-beta, is the activation of E2F.