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EMBO J October 15, 2002; 21 (20): 5417-26.
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SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway.

Oswald F , Kostezka U , Astrahantseff K , Bourteele S , Dillinger K , Zechner U , Ludwig L , Wilda M , Hameister H , Knöchel W , Liptay S , Schmid RM .

Notch proteins are the receptors for an evolutionarily highly conserved signalling pathway that regulates numerous cell fate decisions during development. Signal transduction involves the presenilin-dependent intracellular processing of Notch and nuclear translocation of the intracellular domain of Notch, Notch-IC. Notch-IC associates with the DNA-binding protein RBP-Jkappa/CBF-1 to activate transcription of Notch target genes. In the absence of Notch signalling, RBP-Jkappa/CBF-1 acts as a transcriptional repressor through the recruitment of histone deacetylase (HDAC) corepressor complexes. We identified SHARP as an RBP-Jkappa/CBF-1-interacting corepressor in a yeast two-hybrid screen. In cotransfection experiments, SHARP-mediated repression was sensitive to the HDAC inhibitor TSA and facilitated by SKIP, a highly conserved SMRT and RBP-Jkappa-interacting protein. SHARP repressed Hairy/Enhancer of split (HES)-1 promoter activity, inhibited Notch-1-mediated transactivation and rescued Notch-1-induced inhibition of primary neurogenesis in Xenopus laevis embryos. Based on our data, we propose a model in which SHARP is a novel component of the HDAC corepressor complex, recruited by RBP-Jkappa to repress transcription of target genes in the absence of activated Notch.

PubMed ID: 12374742
PMC ID: PMC129081
Article link: EMBO J

Species referenced: Xenopus laevis
Genes referenced: hdac3 ncor2 notch1 snw1

References [+] :
Beatus, Notch and neurogenesis. 1999, Pubmed, Xenbase