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Molecular and Cellular Biology, July 2000, p. 5048-5063, Vol. 20, No. 14
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

Muktar A. Mahajan and Herbert H. Samuels*

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.

* 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.

Molecular and Cellular Biology, July 2000, p. 5048-5063, Vol. 20, No. 14
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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