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Tumor necrosis factor-α induces the expression of DR6, a member of the TNF receptor family, through activation of NF-κB

Oncogene volume 20, pages 7965–7975 (2001)Cite this article

Abstract

The tumor necrosis factor (TNF) receptor family are ligand-regulated transmembrane proteins that mediate apoptosis as well as activation of the transcription factor NF-κB. Exogenous expression of DR6, a recently identified member of the TNF receptor family, induced apoptosis in untransformed or tumor-derived cells and the apoptotic function of DR6 was inhibited by co-expression of Bcl-2, Bcl-xL or the inhibitor-of-apoptosis (IAP) family member, survivin. Expression of a dominant negative mutant of FADD failed to protect from DR6-mediated apoptosis indicating that unlike TNFR1 and Fas, DR6 induced apoptosis via a FADD-independent mechanism. Despite the ability of exogenous DR6 expression to induce apoptosis, DR6 mRNA and protein were found to be elevated in prostate tumor cell lines and in advanced stages of prostate cancer. Analysis of several anti-apoptotic proteins revealed that Bcl-xL levels and serine 32 phosphorylation of IκB, the natural inhibitor of NF-κB, were similarly elevated in cells expressing high levels of DR6, suggesting that NF-κB-regulated survival proteins may protect from DR6-induced apoptosis and that DR6 is a target of NF-κB regulation. Treatment of LnCAP cells with TNF-α resulted in increases in both DR6 mRNA and protein levels, and this induction was suppressed by inhibitors of NF-κB. Similarly, treatment of cells expressing high levels of DR6 with indomethacin and ibuprofen, compounds also known to perturb NF-κB function, resulted in a dose-dependent decrease in DR6 protein and mRNA levels. These results demonstrate that TNF-α signaling induces the expression of a member of its own receptor family through activation of NF-κB.

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Acknowledgements

We thank Dr Eileen White for helpful discussion, Dr Philip Hedge for supplying Bcl-2, Bcl-xL and survivin expression constructs, Dr Angela Flannery and Tracy Mills for assistance with BAC clone isolations, and Lee Hirata and Patricia Sherman for DNA sequencing.

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Author notes

  1. Matthew V Lorenzi

    Present address: Oncology Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 4000, K12-03, Princeton, NJ 08543-4000, USA

  2. Gary M Kasof and Jian J Lu: GM Kasof and JJ Lu contributed equally to this work

Authors and Affiliations

  1. Department of Enabling Science and Technology, AstraZeneca Pharmaceuticals, 3 Biotech Park, One Innovation Drive, Worcester, MA 01605, Massachusetts, USA

    Gary M Kasof, Jian J Lu, Derong Liu, Brenda Speer, Kathleen N Mongan, Bruce C Gomes & Matthew V Lorenzi

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  1. Gary M Kasof
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Correspondence to Gary M Kasof.

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Kasof, G., Lu, J., Liu, D. et al. Tumor necrosis factor-α induces the expression of DR6, a member of the TNF receptor family, through activation of NF-κB. Oncogene 20, 7965–7975 (2001). https://doi.org/10.1038/sj.onc.1204985

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