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Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest

Oncogene volume 18, pages 6411–6418 (1999)Cite this article

Abstract

The TRAIL death receptor KILLER/DR5 is induced by DNA damaging agents in wild-type p53-expressing cells. Here we show that, unlike the p53-target CDK-inhibitor p21WAF1/CIP1, the TRAIL death receptor KILLER/DR5 is only induced in cells undergoing p53-dependent apoptosis and not cell cycle arrest. Thus GM glioblastoma cells carrying an inducible MMTV-driven p53 gene undergo cell cycle arrest and upregulate p21 but not KILLER/DR5 expression upon dexamethasone exposure. WI38 normal lung fibroblasts undergoing cell cycle arrest in response to ionizing irradiation also induce p21 but not KILLER/DR5 gene expression. KILLER/DR5 upregulation is also deficient in irradiated lymphoblastoid cells derived from patients with Ataxia Teleangiectasia suggesting a role for the ATM-p53 pathway in regulating KILLER/DR5 expression after DNA damage. Inhibition of transcription by Actinomycin D blocks both KILLER/DR5 and p21 induction in cells undergoing p53-dependent apoptosis. Our results suggest that the p53-dependent transcriptional induction of KILLER/DR5 death receptor is restricted to cells undergoing apoptosis and not cells undergoing exclusively p53-dependent G1 arrest.

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Acknowledgements

We thank E Mercer for GM cells, B Vogelstein for Ad-p53, Ad-LacZ, and the human p21 probe, and John Reed for the human Bax probe. This work was supported in part by a program project grant #CA75138-01 (WS El-Deiry, T Yen, RD Meng). WS El-Deiry is an Assistant Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Medicine, Laboratory of Molecular Oncology & Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine Philadelphia, 19104, Pennsylvania, PA, USA

    Gen Sheng Wu, Timothy F Burns, E Robert McDonald III, Ray D Meng & Wafik S El-Deiry

  2. Department of Genetics, Laboratory of Molecular Oncology & Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine Philadelphia, 19104, Pennsylvania, PA, USA

    Wafik S El-Deiry

  3. Department of Radiation Oncology, Laboratory of Molecular Oncology & Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine Philadelphia, 19104, Pennsylvania, PA, USA

    Gary Kao

  4. Department of Pathology, Laboratory of Molecular Oncology & Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine Philadelphia, 19104, Pennsylvania, PA, USA

    Ruth Muschel

  5. The Fox Chase Cancer Center, Philadelphia, 19111, Pennsylvania, PA, USA

    Tim Yen

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Wu, G., Burns, T., McDonald III, E. et al. Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest. Oncogene 18, 6411–6418 (1999). https://doi.org/10.1038/sj.onc.1203025

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