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E2F1 induces MRN foci formation and a cell cycle checkpoint response in human fibroblasts

Oncogene volume 25, pages 3258–3266 (2006)Cite this article

Abstract

Deregulation of the Rb/E2F pathway in human fibroblasts results in an E2F1-mediated apoptosis dependent on Atm, Nbs1, Chk2 and p53. Here, we show that E2F1 expression results in MRN foci formation, which is independent of the Nbs1 interacting region and the DNA-binding domain of E2F1. E2F1-induced MRN foci are similar to irradiation-induced foci (IRIF) that result from double-strand DNA breaks because they correlate with 53BP1 and γH2AX foci, do not form in NBS cells, do form in AT cells and do not correlate with cell cycle entry. In fact, we find that in human fibroblasts deregulated E2F1 causes a G1 arrest, blocking serum-induced cell cycle progression, in part through an Nbs1/53BP1/p53/p21WAF1/CIP1 checkpoint pathway. This checkpoint protects against apoptosis because depletion of 53BP1 or p21WAF1/CIP1 increases both the rate and extent of apoptosis. Nbs1 and p53 contribute to both checkpoint and apoptosis pathways. These results suggest that E2F1-induced foci generate a cell cycle checkpoint that, with sustained E2F1 activity, eventually yields to apoptosis. Uncontrolled proliferation due to Rb/E2F deregulation as well as inactivation of both checkpoint and apoptosis programs would then be required for transformation of normal cells to tumor cells.

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Acknowledgements

We thank laboratory members for comments on the manuscript. A grant from the NIH (CA86038) to TFK and (CA90489) to WDC funded this work. HAR was supported by an NIH training grant (5T32 AI09749). Flow facility was supported by the Diabetes Endocrinology Research Center grant DK32520. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA, USA

    F M Frame, M T Pickering & T F Kowalik

  2. Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA, USA

    H A Rogoff & T F Kowalik

  3. Molecular Oncology Program, Tampa, FL, USA

    W D Cress

  4. H. Lee Moffitt Comprehensive Cancer Center, Tampa, FL, USA

    W D Cress

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  1. F M Frame
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  2. H A Rogoff
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  4. W D Cress
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  5. T F Kowalik
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Correspondence to T F Kowalik.

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Frame, F., Rogoff, H., Pickering, M. et al. E2F1 induces MRN foci formation and a cell cycle checkpoint response in human fibroblasts. Oncogene 25, 3258–3266 (2006). https://doi.org/10.1038/sj.onc.1209352

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