The Nuclear Hormone Receptor Coactivator NRC Is a Pleiotropic Modulator Affecting Growth, Development, Apoptosis, Reproduction, and Wound Repair

Abstract

Nuclear hormone receptor coregulator (NRC) is a 2,063-amino-acid coregulator of nuclear hormone receptors and other transcription factors (e.g., c-Fos, c-Jun, and NF-B). We and others have generated C57BL/6-129S6 hybrid (C57/129) NRC ؉/؊ mice that appear outwardly normal and grow and reproduce. In contrast, homozygous deletion of the NRC gene is embryonic lethal. NRC ؊/؊ embryos are always smaller than NRC ؉/؉ embryos, and NRC ؊/؊ embryos die between 8.5 and 12.5 days postcoitus (dpc), suggesting that NRC has a pleotrophic effect on growth. To study this, we derived mouse embryonic fibroblasts (MEFs) from 12.5-dpc embryos, which revealed that NRC ؊/؊ MEFs exhibit a high rate of apoptosis. Furthermore, a small interfering RNA that targets mouse NRC leads to enhanced apoptosis of wild-type MEFs. The finding that C57/129 NRC ؉/؊ mice exhibit no apparent phenotype prompted us to develop 129S6 NRC ؉/؊ mice, since the phenotype(s) of certain gene deletions may be strain dependent. In contrast with C57/129 NRC ؉/؊ females, 20% of 129S6 NRC ؉/؊ females are infertile while 80% are hypofertile. The 129S6 NRC ؉/؊ males produce offspring when crossed with wild-type 129S6 females, although fertility is reduced. The 129S6 NRC ؉/؊ mice tend to be stunted in their growth compared with their wild-type littermates and exhibit increased postnatal mortality. Lastly, both C57/129 NRC ؉/؊ and 129S6 NRC ؉/؊ mice exhibit a spontaneous wound healing defect, indicating that NRC plays an important role in that process. Our findings reveal that NRC is a coregulator that controls many cellular and physiologic processes ranging from growth and development to reproduction and wound repair.

Regulation of Insulin Secretion and β-Cell Mass by Activating Signal Cointegrator 2

“…We also found that apoptosis was increased and proliferation was decreased in the ASC-2 ϩ/Ϫ islets. The involvement of ASC-2 in the apoptotic process has been suggested previously by two other groups (35,43). ASC-2 Ϫ/Ϫ mouse embryo fibroblasts grow at a reduced rate and exhibit apoptosis.…”

“…ASC-2 Ϫ/Ϫ mouse embryo fibroblasts grow at a reduced rate and exhibit apoptosis. This apoptosis is inhibited by zVAD-fmk, an irreversible pancaspase inhibitor, suggesting a role for caspases in the apoptosis of ASC-2 Ϫ/Ϫ MEFs (35). The other group reported a slight increase of apoptosis in the terminal end buds of ASC-2-deficient mammary glands relative to wild-type mammary glands (43).…”

“…The C-terminal NR box specifically interacts with liver X receptors (LXRs), whereas the N-terminal NR box binds numerous other NRs. ASC-2 null embryos exhibited growth retardation, hypoplastic heart development, defective placentation, and embryonic lethality between 8.5 and 12.5 days postcoitus (2,28,35,61); this indicates that ASC-2 is an important coactivator molecule in vivo, especially in embryonic development. However, because of this early lethality, the use of these knockout mice in further studies of the physiological functions of ASC-2 has been limited.…”

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

“…To establish potentially interrelated functions of ASC2 and MLL3/4, we have used a variety of in vitro and in vivo assays (8,19,30). Interestingly, our recent analysis of a homozygous mouse line that expresses an enzymatically inactivated mutant form of MLL3 demonstrated genetic interactions between ASC-2 and MLL3 (8,15). Therefore, and because these animals show only a partial embryonic lethality (8) as opposed to the early embryonic lethality of ASC-2-null mice (1), they serve as an excellent model system to study the physiological function of ASCOM.…”

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

“…MLL3 ⌬/⌬ mice also show decreased white adipose tissue (WAT), as described here, and kidney ureter urothelium tumors (unpublished results) and resistance to high-fat diet-induced fatty liver formation (27). The early embryonic lethality of ASC-2-null mice (20)(21)(22)26) versus the milder phenotypes of MLL3 ⌬/⌬ mice, along with the demonstrated association of ASC-2 with MLL3 or MLL4 in ASCOM (5, 10) and the overlapping phenotypes of isogenic ASC-2 ϩ/Ϫ mice (26) and MLL3 ⌬/⌬ mice (10), suggest that many ASC-2-target genes are likely to be regulated by MLL3 and MLL4 in a redundant manner. Indeed, our recent results have shown that ASCOM-MLL3 and ASCOM-MLL4 appear to be redundant coactivators both for the tumor suppressor p53 (unpublished results) and the liver X receptor (LXR) and retinoic acid receptor (RAR) (10,27).…”