Abstract
TRAIL (tumour-necrosis factor-related apoptosis ligand or Apo2L) triggers apoptosis through engagement of the death receptors TRAIL-R1 (also known as DR4) and TRAIL-R2 (DR5). Here we show that the c-Rel subunit of the transcription factor NF-κB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the inhibitory protein IκBα or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-κB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-κB also increases expression of the apoptosis inhibitor, Bcl-xL, and protects cells from TRAIL. Inhibition of NF-κB by blocking activation of the IκB kinase complex reduces Bcl-xL expression and sensitizes tumour cells to TRAIL-induced apoptosis. The ability to induce death receptors or Bcl-xL may explain the dual roles of NF-κB as a mediator or inhibitor of cell death during immune and stress responses.
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Acknowledgements
We thank B. Vogelstein for the p53+/+ and p53−/− HCT116 cells; T. Jacks for the p53−/− MEFs; W. El-Deiry for the vector encoding KILLER/DR5; A. A. Beg for providing RelA−/− mouse fibroblasts; S. Gerondakis and C. Snapper for providing c-Rel−/− fibroblasts and c-Rel−/− mice; and K. Bhalla for the HL-60-Neo and HL-60-Bcl-xL cells. This work was funded in part by grants from the NIH (National Cancer Institute), the US Army Medical Research and Materiel Command, Department of Defense Breast Cancer Research Program, and the American Cancer Society (to A.B.). A.B. is a recipient of Physician Scientist award from the Passano Foundation and a Scholar award from the Valvano Foundation for Cancer Research.
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Ravi, R., Bedi, G., Engstrom, L. et al. Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-κB. Nat Cell Biol 3, 409–416 (2001). https://doi.org/10.1038/35070096
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DOI: https://doi.org/10.1038/35070096
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