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SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway
Franz Oswald1, Ulrike Kostezka, Kathy Astrahantseff
1Department of Internal Medicine and Pediatrics, University of Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany.
The EMBO Journal
|October 11, 2002
Summary
SHARP is identified as a novel corepressor in Notch signaling. It works with RBP-Jkappa and histone deacetylase complexes to repress gene transcription when Notch signaling is absent.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Signaling
Background:
- The Notch signaling pathway is crucial for cell fate determination during development.
- Signal transduction involves Notch intracellular domain (Notch-IC) processing and nuclear translocation.
- RBP-Jkappa/CBF-1 binds Notch-IC to activate target genes or acts as a repressor via histone deacetylase (HDAC) complexes in the absence of Notch signaling.
Purpose of the Study:
- To identify novel components of the Notch signaling pathway involved in transcriptional repression.
- To elucidate the role of SHARP in the RBP-Jkappa/CBF-1 mediated repression complex.
Main Methods:
- Yeast two-hybrid screening to identify interacting proteins.
- Cotransfection experiments to assess transcriptional activity.
- Inhibition assays using Trichostatin A (TSA).
- Xenopus laevis embryo experiments to study neurogenesis.
Main Results:
- SHARP was identified as an RBP-Jkappa/CBF-1-interacting corepressor.
- SHARP-mediated repression is HDAC-dependent and facilitated by SKIP.
- SHARP repressed HES-1 promoter activity and Notch-1-mediated transactivation.
- SHARP rescued Notch-1-induced inhibition of neurogenesis in Xenopus embryos.
Conclusions:
- SHARP is a novel component of the HDAC corepressor complex.
- SHARP is recruited by RBP-Jkappa to repress target gene transcription in the absence of activated Notch signaling.
- This finding provides new insights into the regulatory mechanisms of Notch signaling during development.