NF-κB inhibits T-cell activation-induced, p73-dependent cell death by induction of MDM2
Edited by Tak Wah Mak, The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute at Princess Margaret Hospital, University Health Network, Toronto, ON, Canada, and approved September 8, 2010 (received for review May 5, 2010)
Abstract
NF-κB is a key transcription factor involved in the regulation of T-cell activation and proliferation upon engagement of the T-cell receptor (TCR). T cells that lack the IκB kinase (IKKβ) are unable to activate NF-κB, and rapidly undergo apoptosis upon activation. NF-κB activation following T-cell receptor engagement induces the expression of Mdm2 through interaction with NF-κB sites in its P1 promoter, and enforced expression of Mdm2 protected T cells deficient for NF-κB activation from activation-induced cell death. In T cells with intact NF-κB signaling, ablation or pharmacologic inhibition of Mdm2 resulted in activation-induced apoptosis. Mdm2 coprecipitates with p73 in activated T cells, and apoptosis induced by inhibition of Mdm2 was p73-dependent. Further, Bim was identified as a p73 target gene required for cell death induced by Mdm2 inhibition, and a p73-responsive element in intron 1 of Bim was characterized. Our results demonstrate a pathway for survival of activated T cells through NF-κB–induced Mdm2, which blocks Bim-dependent apoptosis through binding and inhibition of p73.
Acknowledgments
We thank Emmanuel Dejardin, Scott Brown, Jean-François Peyron, Ulrich Maurer, Martina Malatesta, and A. Emre Sayan for their valuable scientific support. This work was supported by grants from the National Institutes of Health and Medical Research Council (United Kingdom), Ministero Sanità “Alleanza Contro il Cancro” Grant ACC12, Associazione Italiana per la Ricerca sul Cancro Grant 2008-2010_33-08, and Telethon Grant GGPO4110.
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Published online: October 4, 2010
Published in issue: October 19, 2010
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Acknowledgments
We thank Emmanuel Dejardin, Scott Brown, Jean-François Peyron, Ulrich Maurer, Martina Malatesta, and A. Emre Sayan for their valuable scientific support. This work was supported by grants from the National Institutes of Health and Medical Research Council (United Kingdom), Ministero Sanità “Alleanza Contro il Cancro” Grant ACC12, Associazione Italiana per la Ricerca sul Cancro Grant 2008-2010_33-08, and Telethon Grant GGPO4110.
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This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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NF-κB inhibits T-cell activation-induced, p73-dependent cell death by induction of MDM2, Proc. Natl. Acad. Sci. U.S.A.
107 (42) 18061-18066,
https://doi.org/10.1073/pnas.1006163107
(2010).
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