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  • Original Paper
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Direct repression of the Mcl-1 promoter by E2F1

Oncogene volume 21, pages 1359–1369 (2002)Cite this article

Abstract

E2F1 induces apoptosis via both p53-dependent and p53-independent mechanisms. The direct targets in the p53-independent pathway remain enigmatic; however, the induction of this pathway does not require the transactivation domain of E2F1. Using cells that are defective in p53 activation, we show that E2F1 potently represses the expression of Mcl-1 – an anti-apoptotic Bcl-2 family member whose depletion results in apoptosis. We also show that this transcriptional repression is direct and dependent upon E2F1's DNA-binding domain, but does not require the transactivation domain of E2F1. Consistent with this DNA binding requirement of E2F1 to repress Mcl-1, we show that E2F1 binds to the Mcl-1 promoter both in vitro and in vivo, and have identified the DNA element (−143/−117) within this promoter that is required for E2F1 binding and repression. Additionally, cell lines constitutively expressing Mcl-1 are resistant to E2F1-mediated apoptosis – suggesting that Mcl-1 downregulation is a necessary event in the p53-independent apoptotic process. Thus, we identify a p53 family-independent mechanism of E2F1-induced apoptosis in which E2F1 directly represses Mcl-1 expression.

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Acknowledgements

We thank Ronnie Moorer for technical assistance, Dr Aaron Osborne for helpful advice regarding the ChIP assays, and Drs Richard Jove, Teresita Munoz-Antonia, and PK Burnette for helpful scientific discussion, shared reagents, and comments on the manuscript. We also thank Dr Shrikant Mane, Dr Lanming Zhang and Dr Marybeth Colter, and Jodi Kroeger of Moffitt Core Facilities who performed microarray, DNA sequencing, and flow cytometry experiments, respectively. This work was supported by NCI Grant #CA78214 to WD Cress, by American Heart Association Southern Research Consortium Fellowship #9850018FL to R Croxton, and by the H. Lee Moffitt Cancer Center and Research Institute.

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Authors and Affiliations

  1. Molecular Oncology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida, College of Medicine, Tampa, 33612, Florida, FL, USA

    Rhonda Croxton, Yihong Ma & W Douglas Cress

  2. Clinical Investigations Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida, College of Medicine, Tampa, 33612, Florida, FL, USA

    Lanxi Song & Eric B Haura

  3. Department of Oncology, University of South Florida, College of Medicine, Tampa, 33612, Florida, FL, USA

    Yihong Ma, Lanxi Song, Eric B Haura & W Douglas Cress

  4. Department of Biochemistry and Molecular Biology, University of South Florida, College of Medicine, Tampa, 33612, Florida, FL, USA

    Rhonda Croxton & W Douglas Cress

  5. Institute for Biomolecular Sciences, University of South Florida, College of Medicine, Tampa, 33612, Florida, FL, USA

    Rhonda Croxton & W Douglas Cress

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Correspondence to W Douglas Cress.

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Croxton, R., Ma, Y., Song, L. et al. Direct repression of the Mcl-1 promoter by E2F1. Oncogene 21, 1359–1369 (2002). https://doi.org/10.1038/sj.onc.1205157

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