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Evidence that the human death receptor 4 is regulated by activator protein 1

Oncogene volume 21, pages 3121–3129 (2002)Cite this article

Abstract

Death receptor 4 (DR4; also called TRAIL-R1), a member of the tumor necrosis factor receptor superfamily, is a cell surface receptor that triggers the apoptotic machinery upon binding to its ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Although several chemotherapeutic agents were reported to induce DR4 expression, the mechanism of this effect remains largely unknown. To begin to understand its regulation, we cloned a 1.8 Kb 5′-flanking region of the human DR4 gene and identified several putative binding sites for transcription factors including activator protein 1 (AP-1). Among the three putative AP-1 binding sites, the site located at −350/−344 is functionally active as evidenced by a combination of electrophoretic mobility shift and luciferase reporter assays. The AP-1 activator phorbol 12–myristate 13-acetate (TPA) enhanced the binding of this DR4 AP-1 binding site to protein(s) in a nuclear extract from TPA-treated cells, increased luciferase activity of a reporter construct containing this site and induced DR4 expression at the transcription level. These results indicate that AP-1 regulates DR4 expression via the AP-1 binding site located at −350/−344. AP-1 has been implicated in many critical cellular processes including apoptosis, and is a major target of the c-Jun NH3-terminal kinase signaling pathway that is activated by many anticancer drugs. Therefore, our findings may increase the understanding of the mechanisms underlying AP-1-mediated apoptosis as well as drug-induced apoptosis.

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Acknowledgements

This study was supported in part by the UTMDACC Institutional Research Grant and by a grant from the Prostate Cancer Research Program, The University of Texas, MD Anderson Cancer Center. Sequencing was supported by Cancer Center Core Grant CA16672. We thank Ms Xueyun Chen for her assistance in performing Western blot analysis.

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  1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Baoxiang Guan, Ping Yue, Reuben Lotan & Shi-Yong Sun

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  1. Baoxiang Guan
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Correspondence to Shi-Yong Sun.

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Guan, B., Yue, P., Lotan, R. et al. Evidence that the human death receptor 4 is regulated by activator protein 1. Oncogene 21, 3121–3129 (2002). https://doi.org/10.1038/sj.onc.1205430

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