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Characterization of an E2F1-specific binding domain in pRB and its implications for apoptotic regulation

Oncogene volume 27, pages 1572–1579 (2008)Cite this article

Abstract

The retinoblastoma protein (pRB) has the dual capability to negatively regulate both E2F-induced cell cycle entry and E2F1-induced apoptosis. In this report, we characterize a unique pRB–E2F1 interaction. Using mutagenesis to disrupt E2F1 binding, we find that the ability of pRB to regulate E2F1-induced apoptosis is diminished when this interaction is lost. Strikingly, this mutant form of pRB retains the ability to control E2F responsive cell cycle genes and blocks cell proliferation. These functional properties are the reciprocal of a previously described E2F binding mutant of pRB that interacts with E2F1, but lacks the ability to interact with other E2Fs. Our work shows that these distinct interactions allow pRB to separately regulate E2F-induced cell proliferation and apoptosis. This suggests a novel form of regulation whereby separate types of binding contacts between the same types of molecules can confer distinct functional outcomes.

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Acknowledgements

The authors wish to thank numerous colleagues in the London Regional Cancer Program for helpful discussions in the course of this work. The Strategic Training Program in Cancer Research supported LMJ and LAS. LMJ also thanks the Women's Charity Cashspiel and LAS acknowledges support from OGSST. FAD is a Research Scientist of the NCIC/CCS. Funding from the LHRI (IRF-045-03) and an operating grant from the NCIC/CCS (016191) supported this work.

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Authors and Affiliations

  1. London Regional Cancer Program, University of Western Ontario, London, Ontario, Canada

    L M Julian, O Palander, L A Seifried & F A Dick

  2. Department of Biochemistry, University of Western Ontario, London, Ontario, Canada

    L M Julian, O Palander, L A Seifried, J E G Foster & F A Dick

  3. Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada

    F A Dick

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  1. L M Julian
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  2. O Palander
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  3. L A Seifried
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  4. J E G Foster
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  5. F A Dick
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Correspondence to F A Dick.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Julian, L., Palander, O., Seifried, L. et al. Characterization of an E2F1-specific binding domain in pRB and its implications for apoptotic regulation. Oncogene 27, 1572–1579 (2008). https://doi.org/10.1038/sj.onc.1210803

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