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Development NOTCH1-mediated pathway for NF-KB activity modulation


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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 geneenhancer 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 inB-cells inhibitor ( I-kB ) [1], [2]. V-relreticuloendotheliosis viral oncogene homolog ( c-Rel (NF-kB subunit) ) can triggerNotch homolog 1 translocation-associated ( NOTCH1 receptor ) signaling pathway byinducing expression of Jagged1, ligand for Notch receptors [3],[4]. NOTCH1 receptor activated by Jagged1 or Delta-like1 ( DLL1 ) is cleaved by ADAM metallopeptidase domain 17 ( ADAM17 ) andPresenilin1 to intracellular domain of NOTCH1 ( NOTCH1 (NICD)). NOTCH1 (NICD) is transported to nucleus and participates inrecombination signal binding protein for immunoglobulin kappa J region ( RBP-J kappa(CBF1) )-mediated transcription [5], [4].

RBP-J kappa (CBF1) can act as transcription repressor or activator, dependingon protein complex, which it recruits to DNA [6], [7], [8]. RBP-J kappa (CBF1) acts as gene repressor in a complex withco-repressors Nuclear receptor co-repressor 2 ( SMRT )/Nuclear receptorco-repressor 1 ( N-CoR )/ Histone deacetylase 1 ( HDAC1 ) [9],[7] or CBF1 interacting corepressor ( CIR )/ Sin3A-associated protein30kDa ( SAP30 )/ Histone deacetylase 2 ( HDAC2 ) [9], [7]. HDAC participates in histone deacetylation, which preventstranscription. SMRT and CIR function act as linkers between HDAC andRBP-J kappa (CBF1) via direct binding of linker protein SNW domain containing 1 (SKIP ) [10], [9], [11], [6].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 assistchromatin 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 ofNuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (NFKBIA ) and thus lowers NF-KB activity [4].