NF-κB inhibits T-cell activation-induced, p73-dependent cell death by induction of MDM2

Valere Busuttil, Nathalie Droin, Laura McCormick, Francesca Bernassol, Eleonora Candi, Gerry Melino, Douglas R. Green

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)18061-18066
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number42
DOIs
Publication statusPublished - Oct 19 2010

Keywords

  • Apoptosis
  • Bim
  • T lymphocyte

ASJC Scopus subject areas

  • General

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