Interleukin 1 (IL-1) activates Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-KB) via Interleukin-1 receptor-associated kinase (IRAK) and Mitogen-activated protein kinase kinase kinase 1 (MEKK1(MAP3K1))-dependent inhibition of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (I-kB) [1], [2]. V-rel reticuloendotheliosis viral oncogene homolog (c-Rel (NF-kB subunit)) can trigger Notch homolog 1 translocation-associated (NOTCH1 receptor) signaling pathway by inducing expression of Jagged1, ligand for Notch receptors [3], [4]. NOTCH1 receptor activated by Jagged1 or Delta-like 1 (DLL1) is cleaved by ADAM metallopeptidase domain 17 (ADAM17) and Presenilin1 to intracellular domain of NOTCH1 (NOTCH1 (NICD)). NOTCH1 (NICD) is transported to nucleus and participates in recombination signal binding protein for immunoglobulin kappa J region (RBP-J kappa (CBF1))-mediated transcription [4], [5].

RBP-J kappa (CBF1) can act as transcription repressor or activator, depending on protein complex, which it recruits to DNA [6], [7], [8]. RBP-J kappa (CBF1) acts as gene repressor in a complex with co-repressors Nuclear receptor co-repressor 2 (SMRT)/Nuclear receptor co-repressor 1 (N-CoR)/ Histone deacetylase 1 (HDAC1) [7], [9] or CBF1 interacting corepressor (CIR)/ Sin3A-associated protein 30kDa (SAP30)/ Histone deacetylase 2 (HDAC2) [7], [9]. HDAC participates in histone deacetylation, which prevents transcription. SMRT and CIR function act as linkers between HDAC and RBP-J kappa (CBF1) via direct binding of linker protein SNW domain containing 1 (SKIP) [6], [9], [10], [11]. Intracellular domain of Notch homolog 1 translocation-associated (NOTCH1 (NICD)) binding to SKIP competes with SMRT [6] and, possibly, CIR [7]. NOTCH1 (NICD) recruits Mastermind-like 1 (MAML1), which facilitates E1A binding protein p300 (p300) recruitment. The latter in turn facilitates p300/CBP-associated factor (PCAF) recruitment. Complex MAML1/p300/PCAF acts as histone acetylase and assist chromatin remodeling. NOTCH1 (NICD) competition with RBP-J kappa (CBF1) corepressors determines positive regulation of transcription by NOTCH1 (NICD).

This pathway enables NOTCH1 (NICD) activation of transcription of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (NFKBIA) and thus lowers NF-KB activity [4].

1. Renard P, Raes M
   The proinflammatory transcription factor NFkappaB: a potential target for novel therapeutical strategies. Cell biology and toxicology 1999;15(6):341-4
2. Yao J, Kim TW, Qin J, Jiang Z, Qian Y, Xiao H, Lu Y, Qian W, Gulen MF, Sizemore N, DiDonato J, Sato S, Akira S, Su B, Li X
   Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFkappaB activation pathways bifurcate at IL-1 receptor-associated kinase modification. The Journal of biological chemistry 2007 Mar 2;282(9):6075-89
3. Bash J, Zong WX, Banga S, Rivera A, Ballard DW, Ron Y, Gelinas C
   Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. The EMBO journal 1999 May 17;18(10):2803-11
4. Osipo C, Golde TE, Osborne BA, Miele LA
   Off the beaten pathway: the complex cross talk between Notch and NF-kappaB. Laboratory investigation; a journal of technical methods and pathology 2008 Jan;88(1):11-7
5. Bolos V, Grego-Bessa J, de la Pompa JL
   Notch signaling in development and cancer. Endocrine reviews 2007 May;28(3):339-63
6. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD
   SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. Molecular and cellular biology 2000 Apr;20(7):2400-10
7. Mumm JS, Kopan R
   Notch signaling: from the outside in. Developmental biology 2000 Dec 15;228(2):151-65
8. Kopan R
   Notch: a membrane-bound transcription factor. Journal of cell science 2002 Mar 15;115(Pt 6):1095-7
9. Hsieh JJ, Zhou S, Chen L, Young DB, Hayward SD
   CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proceedings of the National Academy of Sciences of the United States of America 1999 Jan 5;96(1):23-8
10. Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T
    A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes & development 1998 Aug 1;12(15):2269-77
11. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Hayward SD
    A role for SKIP in EBNA2 activation of CBF1-repressed promoters. Journal of virology 2000 Feb;74(4):1939-47