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The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract

Oncogene volume 18, pages 4153–4159 (1999)Cite this article

Abstract

Both DR4 and DR5 have recently been identified as membrane death receptors that are activated by their ligand TRAIL to engage the intracellular apoptotic machinery. TRID (also named as TRAIL-R3) is an antagonist decoy receptor and lacks the cytoplasmic death domain. TRID protects from TRAIL-induced apoptosis by competing with DR4 and DR5 for binding to TRAIL. TRID has been shown to be overexpressed in normal human tissues but not in malignantly transformed cell lines. DR5 is a p53-regulated gene and we have recently reported that DR5 expression is induced in response to genotoxic stress in both a p53-dependent and independent manner (Sheikh et al., 1998). In the current study, we demonstrate that TRID gene expression is also induced by the genotoxic agents ionizing radiation and methyl methanesulfonate (MMS) in predominantly p53 wild-type cells, whereas UV-irradiation does not induce TRID gene expression. Consistent with these results, exogenous wild-type p53 also upregulates the expression of endogenous TRID in p53-null cells. Thus, TRID appears to be a p53 target gene that is regulated by genotoxic stress in a p53-dependent manner. Using primary gastrointestinal tract (GIT) tumors and their matching normal tissue, we also demonstrate for the first time that TRID expression is enhanced in primary tumors of the GIT. It is, therefore, possible that TRID overexpressing GIT tumors may gain a selective growth advantage by escaping from TRAIL-induced apoptosis.

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Acknowledgements

Technical assistance of Kia S Brooks is gratefully acknowledged. SJ Meltzer was supported by NIH grants CA78843, CA77057, DK47717, CA67497 and the office of Medical Research, Department of Veterans Affairs.

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Authors and Affiliations

  1. Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland MD, USA

    M Saeed Sheikh, Sally Amundson & Albert J Fornace Jr

  2. Gene Expression and Aging Section, Laboratory of Biological Chemistry, National Institute on Aging, National Institutes of Health, Baltimore, 21224, Maryland MD, USA

    Ying Huang & Nikki J Holbrook

  3. Laboratory of Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland MD, USA

    Ester A Fernandez-Salas

  4. Laboratory of Molecular Oncology, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania PA, USA

    Wafik S El-Deiry

  5. Department of Visceral and Transplantation Surgery, University of Bern, Inselspital CH-3010 Bern, Switzerland

    Helmut Friess

  6. Department of Medicine, GI Division, University of Maryland at Baltimore and Baltimore VA Hospital, Maryland, 21201, MD, USA

    Jing Yin & Stephen J Meltzer

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  1. M Saeed Sheikh
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Sheikh, M., Huang, Y., Fernandez-Salas, E. et al. The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene 18, 4153–4159 (1999). https://doi.org/10.1038/sj.onc.1202763

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