A new family of nuclear receptor coregulators that integrate nuclear receptor signaling through CREB-binding protein.
We describe the cloning and characterization of a new family of nuclear receptor coregulators (NRCs) which modulate the function of nuclear hormone receptors in a ligand-dependent manner. NRCs are expressed as alternatively spliced isoforms which may exhibit different intrinsic activities and receptor specificities. The NRCs are organized into several modular ... structures and contain a single functional LXXLL motif which associates with members of the steroid hormone and thyroid hormone/retinoid receptor subfamilies with high affinity. Human NRC (hNRC) harbors a potent N-terminal activation domain (AD1), which is as active as the herpesvirus VP16 activation domain, and a second activation domain (AD2) which overlaps with the receptor-interacting LXXLL region. The C-terminal region of hNRC appears to function as an inhibitory domain which influences the overall transcriptional activity of the protein. Our results suggest that NRC binds to liganded receptors as a dimer and this association leads to a structural change in NRC resulting in activation. hNRC binds CREB-binding protein (CBP) with high affinity in vivo, suggesting that hNRC may be an important functional component of a CBP complex involved in mediating the transcriptional effects of nuclear hormone receptors.
Mesh Terms:
Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, CREB-Binding Protein, Cloning, Molecular, Dimerization, Herpes Simplex Virus Protein Vmw65, Hormones, Humans, Intracellular Signaling Peptides and Proteins, Ligands, Molecular Sequence Data, Mutation, Nuclear Proteins, Nuclear Receptor Coactivators, Protein Conformation, Rats, Receptors, Cytoplasmic and Nuclear, Response Elements, Sequence Homology, Amino Acid, Signal Transduction, Trans-Activators, Transcription Factors, Transcription, Genetic
Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, CREB-Binding Protein, Cloning, Molecular, Dimerization, Herpes Simplex Virus Protein Vmw65, Hormones, Humans, Intracellular Signaling Peptides and Proteins, Ligands, Molecular Sequence Data, Mutation, Nuclear Proteins, Nuclear Receptor Coactivators, Protein Conformation, Rats, Receptors, Cytoplasmic and Nuclear, Response Elements, Sequence Homology, Amino Acid, Signal Transduction, Trans-Activators, Transcription Factors, Transcription, Genetic
Mol. Cell. Biol.
Date: Jul. 01, 2000
PubMed ID: 10866662
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