Sharp, an inducible cofactor that integrates nuclear receptor repression and activation.

Area of Science:

• Molecular Biology
• Gene Regulation
• Nuclear Receptor Signaling

Background:

• Nuclear receptor corepressors play critical roles in gene transcription.
• The SMRT (nuclear receptor corepressor) protein is a key component in transcriptional repression.
• Understanding novel interacting partners of SMRT is crucial for elucidating complex regulatory pathways.

Purpose of the Study:

• To identify novel proteins interacting with the nuclear receptor corepressor SMRT.
• To characterize the function and interaction domains of the newly identified protein, SHARP.
• To investigate the role of SHARP in nuclear receptor-mediated transcription and its regulation.

Main Methods:

• Yeast two-hybrid screening was employed to identify SMRT-interacting proteins.
• Co-immunoprecipitation and Western blotting were used to confirm protein interactions.
• Functional assays were performed to assess transcriptional repression activity and RNA binding capabilities.

Main Results:

• A novel human gene, SHARP (SMRT/HDAC1 Associated Repressor Protein), was identified.
• SHARP directly interacts with SMRT and components of the NuRD complex (HDAC1, HDAC2).
• SHARP possesses an RNA binding domain and represses SRA-mediated transcription, impacting both liganded and non-liganded nuclear receptors.
• SHARP expression is steroid-inducible, indicating a feedback regulatory loop.

Conclusions:

• SHARP is a potent transcriptional repressor that modulates nuclear receptor activity through interactions with SMRT, NuRD, and SRA.
• The steroid-inducible expression of SHARP suggests a mechanism for attenuating hormonal responses.
• SHARP represents a significant new player in the complex network of nuclear receptor regulation.