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Role for the double-stranded RNA activated protein kinase PKR in E2F-1-induced apoptosis

Oncogene volume 21, pages 6278–6288 (2002)Cite this article

Abstract

The transcription factor E2F-1 induces cell cycle progression at the G1/S checkpoint, and deregulation of E2F-1 provokes apoptosis in a wide variety of malignant cells. To date only p14ARF and p73, a p53 homologue, have been identified as E2F-1-inducible genes capable of mediating an apoptotic response. Here we show that adenovirus-mediated E2F-1 overexpression in cancer cells induces expression and autophosphorylation of the double-stranded RNA-dependent protein kinase PKR leading to phosphorylation of its downstream target, the α-subunit of the eukaryotic translation initiation factor 2 (eIF-2α) and to apoptotic cell death. This PKR-dependent apoptosis occurs in cell lines with mutated p53 and in cell lines with mutated p53 and p73, and is significantly reduced by the chemical inhibition of PKR activation. Further, PKR−/− mouse embryo fibroblasts, but not PKR+/+ mouse embryo fibroblasts, demonstrate significant resistance to E2F-1-induced apoptosis. We conclude that an important pathway of E2F-1-mediated apoptosis is dependent on PKR activation and does not require p53 or p73.

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Acknowledgements

The authors are grateful to Dr Jian Gu (University of Texas M.D. Anderson Cancer Center) for his help with real-time PCR; Stephanie Deming for her editorial assistance and Mary Elliott for preparation of the manuscript. This investigation was supported in part by the University of Texas M.D. Anderson Cancer Center Support Core Grant (CA 16672), from the National Institute of Health, Department of Health & Human Services, the Department of Defense DAMD17-97-1-7162 (KK Hunt), and the Swiss Cancer League grant BIL SKL 1129-02-2001; and the Foundation for Cancer Treatment grant 148 (SA Vorburger).

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Author notes

  1. Stephan A Vorburger, Abujiang Pataer, Stephen G Swisher and Kelly K Hunt: These authors and laboratories contributed equally to the work

Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Stephan A Vorburger, Paul Chiao, Lee M Ellis & Kelly K Hunt

  2. Department of Thoracic & Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Abujiang Pataer & Stephen G Swisher

  3. Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Weiya Xia & Mien-Chie Hung

  4. Department of Surgery, The Jikei University, School of Medicine, Tokyo, 105, Japan

    Kazumi Yoshida

  5. Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, 33136, Florida, FL, USA

    Glen N Barber

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  1. Stephan A Vorburger
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Correspondence to Kelly K Hunt.

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Vorburger, S., Pataer, A., Yoshida, K. et al. Role for the double-stranded RNA activated protein kinase PKR in E2F-1-induced apoptosis. Oncogene 21, 6278–6288 (2002). https://doi.org/10.1038/sj.onc.1205761

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  • DOI: https://doi.org/10.1038/sj.onc.1205761

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