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First published online on November 23, 2004
First published online on December 7, 2004
Endocrine Reviews, doi:10.1210/er.2004-0012
A more recent version of this article appeared on June 1, 2005
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*Hormones

Nuclear Hormone Receptor Co-regulator (NRC): Role in hormone action, metabolism, growth, and development

Muktar A. Mahajan and Herbert H. Samuels*

Herbert H. Samuels Departments of Pharmacology and Medicine New York University School of Medicine 550 First Avenue, New York, NY 10016 USA

* To whom correspondence should be addressed. E-mail: herbert.samuels{at}med.nyu.edu.

NRC (also referred to as ASC-2, TRBP, PRIP, and RAP250) belongs to a growing class of nuclear co-factors widely known as co-regulators or co-activators that are necessary for transcriptional activation of target genes. The NRC gene is also amplified and overexpresed in breast, colon and lung cancers. NRC is a 2063 amino acid protein which harbors a potent N-terminal activation domain (AD1) and a second more centrally located activation domain (AD2) which is rich in Glu and Pro. Near AD2 is a receptor interacting domain containing an LxxLL motif (LxxLL-1) which interacts with a wide variety of ligand-bound NRs with high-affinity. A second LxxLL motif (LxxLL-2) located in the C-terminal region of NRC is more restricted in its NR specificity. The intrinsic activation potential of NRC is regulated by a C-terminal STL regulatory domain. The potential role of NRC as a co-integrator is suggested by its ability to enhance transcriptional activation of a wide variety of transcription factors and from its in vivo association with a number of known transcriptional regulators including CBP/p300. Recent studies in mice indicate that deletion of both NRC alleles leads to embryonic lethality resulting from general growth retardation coupled with developmental defects in the heart, liver, brain and placenta. NRC-/- MEFs spontaneously undergo apoptosis indicating the importance of NRC as a prosurvival and anti-apoptotic gene. Studies with 129S6 NRC+/- mice indicate that NRC is a pleiotropic regulator which is involved in growth, development, reproduction, metabolism, and wound healing.
Key words: NRC • co-activator • nuclear hormone receptor • co-regulator • growth • apoptosis • wound healing • reproduction • knockout mice




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