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Expression of the E2F1 transcription factor overcomes type beta transforming growth factor-mediated growth
J K Schwarz1, C H Bassing, I Kovesdi
1Department of Genetics, Duke University Medical Center, Durham, NC 27710.
Abstract:
Inhibition of cell growth by type beta transforming growth factor (TGF-beta) 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-beta 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-beta action. Consistent with that possibility is the observation that E2F1 RNA levels are drastically reduced in TGF-beta-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-beta. We find that overexpression of E2F1 can overcome the TGF-beta-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-beta, is the activation of E2F.
Insights
Type beta transforming growth factor (TGF-beta) inhibits cell growth by reducing cyclin-dependent kinase activity. Overexpressing E2F1 overcomes this inhibition, suggesting E2F1 is a key downstream target of TGF-beta signaling.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Type beta transforming growth factor (TGF-beta) is known to inhibit cell growth during the mid-G1 phase.
- This inhibition is linked to reduced G1 cyclin-dependent kinase activity and the retinoblastoma tumor suppressor protein (Rb) remaining in a growth-suppressive state.
Purpose of the Study:
- To investigate the role of the E2F transcription factor as a downstream target of TGF-beta signaling.
- To determine if controlling E2F activity is a mechanism by which TGF-beta inhibits cell growth.
Main Methods:
- Analyzing E2F1 RNA levels in TGF-beta-treated cells.
- Overexpressing the human E2F1 gene using a recombinant adenovirus in TGF-beta-arrested mink lung epithelial cells.
Main Results:
- E2F1 RNA levels were significantly reduced in cells treated with TGF-beta.
- Overexpression of E2F1 successfully overcame the TGF-beta-mediated growth arrest, as evidenced by the activation of cellular DNA synthesis.
Conclusions:
- The findings strongly suggest that E2F transcription factor activation is a critical downstream event regulated by TGF-beta.
- This study identifies E2F as a likely target for cyclin-dependent kinases modulated by TGF-beta, providing insight into cell cycle control mechanisms.