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Direct repression of the Mcl-1 promoter by E2F1
Rhonda Croxton1, Yihong Ma, Lanxi Song
1Molecular Oncology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida, College of Medicine, Tampa, Florida, FL 33612, USA.
Oncogene
|February 22, 2002
Summary
E2F1 triggers apoptosis independently of p53 by directly repressing the anti-apoptotic Mcl-1 gene. This E2F1-Mcl-1 interaction is crucial for initiating programmed cell death via a novel pathway.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- E2F1 is a transcription factor involved in cell cycle regulation and apoptosis.
- E2F1-induced apoptosis occurs through both p53-dependent and p53-independent pathways.
- The direct targets of E2F1 in the p53-independent apoptotic pathway are not fully understood.
Purpose of the Study:
- To elucidate the direct molecular targets of E2F1 in p53-independent apoptosis.
- To identify the mechanism by which E2F1 induces apoptosis without p53.
- To investigate the role of Mcl-1 in E2F1-mediated apoptosis.
Main Methods:
- Utilized p53-deficient cells to study E2F1's apoptotic mechanisms.
- Performed gene expression analysis to identify E2F1 targets.
- Conducted DNA-binding assays (in vitro and in vivo) to confirm E2F1 interaction with the Mcl-1 promoter.
- Identified the specific DNA element in the Mcl-1 promoter responsible for E2F1 binding and repression.
Main Results:
- E2F1 directly represses the expression of Mcl-1, an anti-apoptotic protein, in a p53-independent manner.
- This repression requires E2F1's DNA-binding domain but not its transactivation domain.
- E2F1 binds to a specific region (-143/-117) of the Mcl-1 promoter.
- Cells with constitutive Mcl-1 expression are resistant to E2F1-induced apoptosis.
Conclusions:
- E2F1 directly represses Mcl-1 expression, leading to apoptosis through a p53-independent pathway.
- Downregulation of Mcl-1 is a critical step in E2F1-mediated apoptosis independent of p53.
- Identified a novel mechanism of E2F1-induced apoptosis involving direct transcriptional repression of Mcl-1.