Development - NOTCH1-mediated pathway for NF-KB activity modulation

NOTCH1-mediated pathway for NF-KB activity modulation

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].

References:

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