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Molecular and Cellular Biology, July 2000, p. 5048-5063, Vol. 20, No. 14
Division of Clinical and Molecular
Endocrinology, Department of Medicine, and Department of
Pharmacology, New York University School of Medicine, New York, New
York 10016
Received 18 February 2000/Returned for modification 4 April
2000/Accepted 14 April 2000
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.
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
A New Family of Nuclear Receptor Coregulators That
Integrate Nuclear Receptor Signaling through CREB-Binding
Protein
*
Corresponding author. Mailing address: Division of
Clinical and Molecular Endocrinology, Department of Medicine, and the
Department of Pharmacology, New York University School of Medicine, 550 First Ave., New York, NY 10016. Phone: (212) 263-6279. Fax: (212)
263-7701. E-mail: hs26{at}is9.nyu.edu.
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