Nuclear Hormone Receptor Coregulator: Role in Hormone Action, Metabolism, Growth, and Development

Abstract

Nuclear hormone receptor coregulator (NRC) (also referred to as activating signal cointegrator-2, thyroid hormone receptor-binding protein, peroxisome proliferator activating receptor-interacting protein, and 250-kDa receptor associated protein) belongs to a growing class of nuclear cofactors widely known as coregulators or coactivators that are necessary for transcriptional activation of target genes. The NRC gene is also amplified and overexpressed in breast, colon, and lung cancers. NRC is a 2063-amino acid protein that harbors a potent N-terminal activation domain (AD1) and a second more centrally located activation domain (AD2) that 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 nuclear hormone receptors with high affinity. A second LxxLL motif (LxxLL-2) located in the C-terminal region of NRC is more restricted in its nuclear hormone receptor specificity. The intrinsic activation potential of NRC is regulated by a C-terminal serine, threonine, leucine-regulatory domain. The potential role of NRC as a cointegrator 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(-/-) mouse embryo fibroblasts spontaneously undergo apoptosis, indicating the importance of NRC as a prosurvival and antiapoptotic gene. Studies with 129S6 NRC(+/-) mice indicate that NRC is a pleiotropic regulator that is involved in growth, development, reproduction, metabolism, and wound healing.

Targeted inactivation of MLL3 histone H3–Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis

“…ASC-2, a distinct subunit in ASCOM, has been proposed as a key adaptor used by many members of the nuclear receptor superfamily to recruit ASCOM (9). Indeed, we have shown that ASC-2 is an essential adaptor for recruitment of ASCOM by RARs and LXRs (10,27).…”

“…Activating signal cointegrator-2 (ASC-2; also named NCOA6, AIB3, TRBP, TRAP250, NRC, and PRIP) is a coactivator of numerous nuclear receptors and transcription factors (9). Importantly, ASC-2 is an integral and unique component of a Set1-like complex named ASCOM (for ASC-2 complex), which contains MLL3 or MLL4 (5,10).…”

“…The importance of ASC-2 as a key coactivator of multiple nuclear receptors has been reported from studies with various ASC-2 mouse models (9,17). In particular, ASC-2-null mice display at least 2 major phenotypes comparable with those described for mice with targeted inactivation of the peroxisome proliferator-activated receptor ␥ (PPAR␥) and its dimerization partner retinoid X receptor (18,19).…”

A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4

“…A ctivating signal cointegrator-2 (ASC-2; also named AIB3, TRBP, TRAP250, NRC, NCOA6, and PRIP) is a coactivator of numerous nuclear receptors, and other transcription factors (1). Its physiological importance as a key coactivator, most notably for several nuclear receptors, has been demonstrated in studies with various ASC-2 mouse models (1,2).…”

Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity

“…This mediator complex is anchored by peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP) (4), which also is known as TRAP220͞vitamin D receptor-interacting protein 205͞ mediator 1 (MED1) (3,5,6). Identification in recent years of many nuclear-receptor coactivators and coactivator-binding proteins raises questions about their functional role in gene, cell, and stage-specific transcription (2,3,(7)(8)(9)(10)(11). Accordingly, delineation of the in vivo functional roles of these transcriptional coactivators becomes an important challenge.…”