Coactivator PRIP, the Peroxisome Proliferator-activated Receptor-interacting Protein, Is a Modulator of Placental, Cardiac, Hepatic, and Embryonic Development

Abstract

Nuclear receptor coactivator PRIP (peroxisome proliferator-activated receptor (PPAR␥)-interacting protein) and PRIP-interacting protein with methyltransferase activity, designated PIMT, appear to serve as linkers between cAMP response element-binding protein-binding protein (CBP)/p300-anchored and PBP (PPAR␥-binding protein)-anchored coactivator complexes involved in the transcriptional activity of nuclear receptors. To assess the biological significance of PRIP, we disrupted the PRIP gene in mice by homologous recombination. Mice nullizygous for PRIP died between embryonic day 11.5 and 12.5 (postcoitum) due in most part to defects in the development of placenta, heart, liver, nervous system, and retardation of embryonic growth. Transient transfection assays using fibroblasts isolated from PRIP ؊/؊ embryos revealed a significant decrease in the capacity for ligand-dependent transcriptional activation of retinoid X receptor ␣ and to a lesser effect on PPAR␥ transcriptional activity. These observations indicate that PRIP like PBP, CBP, and p300 is an essential and nonredundant coactivator.Our understanding of the mechanisms underlying transcriptional activation by nuclear receptors has been advanced by the identification of nuclear receptor coactivators or coregulators that appear to influence embryonic development, cell proliferation, and differentiation (1). These include p160/SRC-1 1 (steroid receptor coactivator-1) family with three members (SRC-1, TIF/GRIP1/SRC-2, and pCIP/AIB1/ACTR/RAC3/TRAM1/SRC3) (2-6), CREB-binding protein (CBP) (7), adenovirus E1A-binding protein p300 (8), peroxisome proliferator-activated receptor-␥ (PPAR␥)-binding protein (PBP) (9), PPAR-interacting protein (PRIP/ASC-2/RAP250/TRBP/NRC) (10 -14) and PPAR␥ coactivator-1 (PGC-1) (15), among others. Nuclear receptor coactivators contain one or more conserved LXXLL (where L is leucine and X any amino acid) signature motif, which has been found to be necessary and sufficient for ligand-dependent interactions with the activation function-2 domain present in the C-terminal hormone-binding region of the nuclear receptors (1, 6). It is generally held that coactivators play a central role in mediating nuclear receptor transcriptional activity by functioning as at least two large multiprotein complexes formed either sequentially or combinatorially (1). The first complex anchored by CBP/p300 and containing p/160 cofactors/SRC-1 cofactors exhibits histone acetyltransferase activity necessary for remodeling chromatin (1,4,7,16), while the second multiprotein complex, variously referred to as TRAP/DRIP/ARC mediator complex, which is anchored by PBP (17-19), facilitates interaction with RNA polymerase II complexes of the basal transcription machinery (1). Deletion of CBP/p300 and PBP genes in the mouse results in embryonic lethality around E11.5 days, indicating that disruption of these pivotal anchoring coactivators affects the integrity of the cofactor complexes, thus altering the function of many nuclear receptors and most likely of other transcript...

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

“…Chimeric male mice derived from C57BL/6 blastocysts and NRC ϩ/Ϫ embryonic stem (ES) cells (129S6 background) were crossed with C57BL/6 females to obtain NRC ϩ/Ϫ mice in a mixed background (indicated as C57/129). As previously reported, the NRC Ϫ/Ϫ mutation is embryonic lethal and no NRC Ϫ/Ϫ mice are born while NRC ϩ/Ϫ mice in the mixed C57/129 background are viable and able to reproduce (2,32,73). We have observed these NRC ϩ/Ϫ mice over a 2-year period and have noted that they develop an interesting phenotype associated with chronic wound healing.…”

“…The following findings summarize these results. CBP Ϫ/Ϫ , p300 Ϫ/Ϫ , TRAP220 Ϫ/Ϫ , and NRC Ϫ/Ϫ mice are embryonic lethal (2,20,26,32,33,57,68,73). TRAP220 ϩ/Ϫ mice are viable but exhibit pituitary hypothyroidism.…”

“…In addition to NRs, NRC also activates a variety of other transcription factors, such as c-Fos and c-Jun (31,34,40,41). Mice null for expression of NRC have been recently reported by three different laboratories (2,32,73). Deletion of the NRC gene in mice revealed that null mutants (NRC Ϫ/Ϫ ) die during early stages of embryogenesis (9.75 to 13.5 dpc) while mice heterozygous for the NRC gene (NRC ϩ/Ϫ ) in a mixed genetic background (C57/129) appear to be normal in growth and development.…”

“…Deletion of the NRC gene in mice revealed that null mutants (NRC Ϫ/Ϫ ) die during early stages of embryogenesis (9.75 to 13.5 dpc) while mice heterozygous for the NRC gene (NRC ϩ/Ϫ ) in a mixed genetic background (C57/129) appear to be normal in growth and development. Intrauterine death of NRC-null embryos has been attributed to placental dysfunction, cardiac hypoplasia, and liver dysfunction, among other changes (2,32,73). Null PRIP MEFs in culture also fail to undergo adipocyte differentiation (53).…”

Haploid Inactivation of the Amplified-in-Breast Cancer 3 Coactivator Reduces the Inhibitory Effect of Peroxisome Proliferator-Activated Receptor γ and Retinoid X Receptor on Cell Proliferation and Accelerates Polyoma Middle-T Antigen-Induced Mammary Tumorigenesis in Mice

“…We and others have shown that inactivation of both of the AIB3 alleles in mice results in embryonic lethality due to defects in placental, cardiac, and hepatic development (23)(24)(25). These phenotypes are similar to those encountered in mice lacking PPAR␥ or PPAR␥-binding protein (26,27).…”