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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2018.9
- 수록면
- 842 - 852 (11page)
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초록· 키워드
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Notch signaling is an evolutionarily conserved pathway and involves in the regulation of various cellular and developmental processes. Ligand binding releases the intracellular domain of Notch receptor (NICD), which interacts with DNA-bound CSL [CBF1/Su(H)/Lag-1] to activate transcription of target genes. In the absence of NICD binding, CSL down-regulates target gene expression through the recruitment of various corepressor proteins including SMRT/NCoR (silencing mediator of retinoid and thyroid receptors/nuclear receptor corepressor), SHARP (SMRT/HDAC1-associated repressor protein), and KyoT2. Structural and functional studies revealed the molecular basis of these interactions, in which NICD coactivator and corepressor proteins competitively bind to β-trefoil domain (BTD) of CSL using a conserved ?W?P motif (? denotes any hydrophobic residues). To date, there are conflicting ideas regarding the molecular mechanism of SMRT-mediated repression of CSL as to whether CSL-SMRT interaction is direct or indirect (via the bridge factor SHARP). To solve this issue, we mapped the CSL-binding region of SMRT and employed a 'one- plus two-hybrid system' to obtain CSL interaction-defective mutants for this region. We identified the CSL-interaction module of SMRT (CIMS; amino acid 1816-1846) as the molecular determinant of its direct interaction with CSL. Notably, CIMS contains a canonical ?W?P sequence (APIWRP, amino acids 1832-1837) and directly interacts with CSL-BTD in a mode similar to other BTD-binding corepressors. Finally, we showed that CSL-interaction motif, rather than SHARP-interaction motif, of SMRT is involved in transcriptional repression of NICD in a cell-based assay. These results strongly suggest that SMRT participates in CSL-mediated repression via direct binding to CSL.
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참고문헌 (29)
참고문헌 신청
Ann, E.J. / 2012 / Wnt5a controls Notch1 signaling through CaMKII-mediated degradation of the SMRT corepressor protein / J. Biol. Chem. 287:36814~36829
Ariyoshi, M. / 2003 / A conserved structural motif reveals the essential transcriptional repression function of Spen proteins and their role in developmental signaling / Genes Dev. 17:1909~1920
Borggrefe, T. / 2009 / The Notch signaling pathway: transcriptional regulation at Notch target genes / Cell. Mol. Life Sci. 66:1631~1646
Borggrefe, T. / 2014 / Keeping notch target genes off: a CSL corepressor caught in the act / Structure 22:3~5
Borggrefe, T. / 2016 / Setting the stage for notch: The Drosophila Su(H)-hairless repressor complex / PLoS Biol. 14:e1002524
Ariyoshi, M. / 2003 / A conserved structural motif reveals the essential transcriptional repression function of Spen proteins and their role in developmental signaling / Genes Dev. 17:1909~1920
Borggrefe, T. / 2009 / The Notch signaling pathway: transcriptional regulation at Notch target genes / Cell. Mol. Life Sci. 66:1631~1646
Borggrefe, T. / 2014 / Keeping notch target genes off: a CSL corepressor caught in the act / Structure 22:3~5
Borggrefe, T. / 2016 / Setting the stage for notch: The Drosophila Su(H)-hairless repressor complex / PLoS Biol. 14:e1002524
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