Notch1 augments NF-kappaB activity by facilitating its nuclear retention.

TitleNotch1 augments NF-kappaB activity by facilitating its nuclear retention.
Publication TypeJournal Article
Year of Publication2006
AuthorsShin, HMu, Minter, LM, Cho, OHyun, Gottipati, S, Fauq, AH, Golde, TE, Sonenshein, GE, Osborne, BA
JournalThe EMBO journal
Date Published2006 Jan 11
AbstractNotch1 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.
Alternate JournalEMBO J.