| First Author | Shin HM | Year | 2006 |
| Journal | EMBO J | Volume | 25 |
| Issue | 1 | Pages | 129-38 |
| PubMed ID | 16319921 | Mgi Jnum | J:104460 |
| Mgi Id | MGI:3612002 | Doi | 10.1038/sj.emboj.7600902 |
| Citation | Shin HM, et al. (2006) Notch1 augments NF-kappaB activity by facilitating its nuclear retention. EMBO J 25(1):129-38 |
| abstractText | 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 (N1(IC)) directly interacts with NF-kappaB and competes with IkappaBalpha, leading to retention of NF-kappaB in the nucleus. Additionally, we show that N1(IC) 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. |
