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p53-dependent radiation-induced crypt intestinal epithelial cells apoptosis is mediated in part through TNF-TNFR1 system

Oncogene volume 20, pages 812–818 (2001)Cite this article

Abstract

Radiation induces apoptosis of crypt intestinal epithelial cells (IEC) through a pathway that is largely dependent on p53. However, exactly how p53 mediates IEC apoptosis is unclear. Studies in vitro suggest that one mechanism by which p53 mediates apoptosis is through its ability to transactivate members of the TNF receptor family of ‘Death Receptors’. Here, we examined the role of one of its member, TNF receptor type 1 (TNFR1), in an in vivo model of p53-dependent radiation-induced IEC apoptosis. We demonstrate that mice genetically engineered to be deficient in TNF receptor type 1 (TNFR1−/−) and mice injected with TNFR1-fusion chimeric protein (TNFR1-Fc; a competitive inhibitor of TNFR1) were partially protected (30–40%) from p53-dependent radiation-induced IEC apoptosis. However, we found no evidence to support the possibility p53 transcriptionally regulates the expression of TNFR1 nor increases the susceptibility of IEC to TNF-mediated apoptosis. Interestingly, we found that injection of TNF readily induced IEC apoptosis and that radiation induced a p53-dependent increase in the intestinal level of TNF. Furthermore, injection of a neutralizing anti-TNF mAb reduced p53-dependent radiation-induced IEC apoptosis by approximately 60%. Overall, these results suggest that p53-dependent radiation-induced IEC apoptosis is mediated in part through ability of p53 to regulate TNF, which subsequently induces IEC apoptosis through TNFR1.

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Abbreviations

TNF:

tumor necrosis factor

IEC:

Intestinal epithelial cells

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Acknowledgements

This work was funded by Howard Hugh Institute award for new investigators at Northwestern University and NIH awards DK02445 and DK56605-01 to T Lin and NIH grant CA69381 to CF Ware, NIH grant AI 44828 to DR Green.

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Authors and Affiliations

  1. Department of Medicine, Section of Gastroenterology, Northwestern University Medical School, Chicago, IL 60611, Illinois, USA

    Kyoko Inagaki-Ohara, Shinichiro Yada, Noriaki Takamura, Xiaohong Yu, Erdong Liu & Tesu Lin

  2. Division of Cellular Immunology, La Jolla Institute of Allergy and Immunology, San Diego, CA 92121, California, USA

    Miriam Reaves, Shelby Nicholas, Arturo Castro & Douglas R Green

  3. Division of Molecular Immunology, La Jolla Institute of Allergy and Immunology, San Diego, CA 92121, California, USA

    Isabelle Rooney & Carl F Ware

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  1. Kyoko Inagaki-Ohara
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  2. Shinichiro Yada
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Inagaki-Ohara, K., Yada, S., Takamura, N. et al. p53-dependent radiation-induced crypt intestinal epithelial cells apoptosis is mediated in part through TNF-TNFR1 system. Oncogene 20, 812–818 (2001). https://doi.org/10.1038/sj.onc.1204172

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