Title | Notch1 augments NF-kappaB activity by facilitating its nuclear retention. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Shin, HMu, Minter, LM, Cho, OHyun, Gottipati, S, Fauq, AH, Golde, TE, Sonenshein, GE, Osborne, BA |
Journal | The EMBO journal |
Volume | 25 |
Issue | 1 |
Pagination | 129-38 |
Date Published | 2006 Jan 11 |
Abstract | 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. |
Alternate Journal | EMBO J. |
Veterinary and Animal Sciences