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E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2
T F Kowalik1, J DeGregori, G Leone
1Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
Previous work has demonstrated a role for E2F transcription factor activity in the regulation of cell growth during the G0/G1-S phase transition. Indeed, overexpression of E2F proteins, including the E2F1 and E2F2 products, induces DNA synthesis in quiescent fibroblasts. Other experiments have shown that E2F1 expression also induces apoptosis, dependent on p53. Although this could represent a response to aberrant cell cycle progression, we show that only E2F1 induces apoptosis and that this coincides with an ability of E2F1 to induce accumulation of p53 protein. We also find that coexpression of Mdm2, which is known to regulate p53 activity, blocks the E2F1-mediated induction of apoptosis and also blocks the E2F1-mediated accumulation of p53. We propose that E2F1 acts as a specific signal for the induction of apoptosis by affecting the accumulation of p53, which under normal proliferative conditions may be controlled by Mdm2.
Insights
E2F1 transcription factor induces apoptosis by increasing p53 protein levels. Mdm2 protein inhibits this E2F1-induced apoptosis and p53 accumulation, suggesting a regulatory role in cell growth and death.
Area of Science:
- Molecular Biology
- Cell Cycle Regulation
- Cancer Research
Background:
- E2F transcription factors regulate cell growth during the G0/G1-S phase transition.
- Overexpression of E2F proteins (E2F1, E2F2) induces DNA synthesis in quiescent cells.
Purpose of the Study:
- Investigate the role of E2F1 in apoptosis induction.
- Determine the relationship between E2F1, p53, and Mdm2 in apoptosis and cell cycle control.
Main Methods:
- Gene overexpression studies in fibroblasts.
- Analysis of p53 protein accumulation.
- Assessment of apoptosis induction.
- Coexpression experiments with Mdm2.
Main Results:
- Only E2F1, not E2F2, induces apoptosis, which correlates with p53 accumulation.
- E2F1-mediated apoptosis and p53 accumulation are blocked by coexpressed Mdm2.
- Mdm2 regulates p53 activity and its role in E2F1-induced apoptosis.
Conclusions:
- E2F1 acts as a specific signal for apoptosis induction via p53 accumulation.
- Mdm2 may control p53 levels and E2F1-mediated apoptosis under normal proliferation.