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Induction of DNA synthesis and apoptosis are separable functions of E2F-1
A C Phillips1, S Bates, K M Ryan
1ABL Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Maryland 21702, USA.
Abstract:
The family of E2F transcription factors have an essential role in mediating cell cycle progression, and recently, one of the E2F protein family, E2F-1, has been shown to participate in the induction of apoptosis. Cooperation between E2F and the p53 tumor suppressor protein in this apoptotic response had led to the suggestion that cell cycle progression induced by E2F-1 expression provides an apoptotic signal when placed in conflict with an arrest to cell cycle progression, such as provided by p53. We show here that although apoptosis is clearly enhanced by p53, E2F-1 can induce significant apoptosis in the absence of p53. Furthermore, this apoptotic function of E2F-1 is separable from the ability to accelerate entry into DNA synthesis. Analysis of E2F-1 mutants indicates that although DNA-binding is required, transcriptional transactivation is not necessary for the induction of apoptosis by E2F-1, suggesting that it may be mediated through alleviation of E2F-dependent transcriptional repression. These results indicate that E2F-1 can show independent cell cycle progression and apoptotic functions, consistent with its putative role as a tumor suppressor.
Insights
E2F-1 transcription factor induces apoptosis independently of p53, separating cell cycle progression and cell death functions. This suggests E2F-1 acts as a tumor suppressor by potentially alleviating transcriptional repression.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- E2F transcription factors regulate cell cycle progression.
- E2F-1 has been implicated in apoptosis induction.
- Cooperation with p53 suggests E2F-1-induced cell cycle progression signals apoptosis when conflicting with cell cycle arrest.
Purpose of the Study:
- To investigate the role of E2F-1 in apoptosis, particularly its independence from p53.
- To determine if E2F-1's apoptotic function is separable from its role in DNA synthesis.
- To elucidate the mechanism by which E2F-1 induces apoptosis.
Main Methods:
- Analysis of E2F-1 mutants.
- Experiments conducted in the presence and absence of p53.
- Assessment of apoptosis induction and cell cycle progression.
Main Results:
- E2F-1 induces significant apoptosis even without p53.
- The apoptotic function of E2F-1 is distinct from its ability to accelerate DNA synthesis.
- DNA-binding is necessary for E2F-1-induced apoptosis, but transcriptional transactivation is not required.
Conclusions:
- E2F-1 possesses independent functions in cell cycle progression and apoptosis.
- E2F-1 may induce apoptosis by alleviating E2F-dependent transcriptional repression.
- These findings support a role for E2F-1 as a tumor suppressor.