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  • The EMBO Journal (2006) 25, 129 - 138
  • doi:10.1038/sj.emboj.7600902

Published online: 1 December 2005

Notch1 augments NF-kappaB activity by facilitating its nuclear retention

Hyun Mu Shin1, Lisa M Minter2, Ok Hyun Cho2, Sridevi Gottipati1, Abdul H Fauq3, Todd E Golde3, Gail E Sonenshein4 and Barbara A Osborne1,2

  1. Molecular and Cellular Biology Program, University of Massachusetts/Amherst, Amherst, MA, USA
  2. Department of Veterinary and Animal Sciences, University of Massachusetts/Amherst, Amherst, MA, USA
  3. Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, FL, USA
  4. Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA

Correspondence to:

Barbara A Osborne, Department of Veterinary and Animal Sciences, 311 Paige Laboratory, University of Massachusetts/Amherst, 161 Holdsworth Way, Amherst, MA 01003, USA. Tel.: +1 413 545 4882; Fax: +1 413 545 1446; E-mail: osborne@vasci.umass.edu

Received 13 September 2005; Accepted 15 November 2005

Notch1 specifically upregulates expression of the cytokine interferon-gamma in peripheral T cells through activation of NF-kappaB. However, how Notch mediates NF-kappaB activation remains unclear. Here, we examined the temporal relationship between Notch signaling and NF-kappaB induction during T-cell activation. NF-kappaB activation occurs within minutes of T-cell receptor (TCR) engagement and this activation is sustained for at least 48 h following TCR signaling. We used gamma-secretase inhibitor (GSI) to prevent the cleavage and subsequent activation of Notch family members. We demonstrate that GSI blocked the later, sustained NF-kappaB activation, but did not affect the initial activation of NF-kappaB. Using biochemical approaches, as well as confocal microscopy, we show that the intracellular domain of Notch1 (N1IC) directly interacts with NF-kappaB and competes with IkappaBalpha, leading to retention of NF-kappaB in the nucleus. Additionally, we show that N1IC can directly regulate IFN-gamma expression through complexes formed on the IFN-gamma promoter. Taken together, these data suggest that there are two 'waves' of NF-kappaB activation: an initial, Notch-independent phase, and a later, sustained activation of NF-kappaB, which is Notch dependent.

  • Keywords:

    • IkappaBalpha,
    • interferon-gamma,
    • NF-kappaB,
    • Notch1