SRC-3 Has a Role in Cancer Other Than as a Nuclear Receptor Coactivator

ABSTRACT Coactivators constitute a diverse group of proteins that are essential for optimal transcriptional activity of nuclear receptors. In the past few years many coactivators have been identified but it is still unclear whether these proteins interact indiscriminately with all nuclear receptors and whether there is some redundancy in their functions. We have previously cloned and characterized RAP250 (ASC-2/PRIP/TRBP/NRC), an LXXLL-containing coactivator for nuclear receptors. In order to study its biological role, Rap250 null mice were generated by gene targeting. Here we show that genetic disruption of Rap250 results in embryonic lethality at embryonic day (E) 13.5. Histological examination of placentas revealed a dramatically reduced spongiotrophoblast layer, a collapse of blood vessels in the region bordering the spongiotrophoblast, and labyrinthine layers in placentas from Rap250−/− embryos. These findings suggest that the lethality of Rap250−/− embryos is the result of obstructed placental blood circulation. Moreover, the transcriptional activity of PPARγ is reduced in fibroblasts derived from Rap250−/− embryos, suggesting that RAP250 is an essential coactivator for this nuclear receptor in the placenta. Our results demonstrate that RAP250 is necessary for placental development and thus essential for embryonic development.

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Proline-Rich Nuclear Receptor Coactivator 1

10.32388/3logkg ◽

2020 ◽

Author(s):

Keyword(s):

Nuclear Receptor ◽

Nuclear Receptor Coactivator

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Identification of a nuclear receptor/coactivator developmental signaling pathway in the nematode parasite Strongyloides stercoralis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2021864118 ◽

2021 ◽

Vol 118 (8) ◽

pp. e2021864118

Author(s):

Mi Cheong Cheong ◽

Zhu Wang ◽

Tegegn G. Jaleta ◽

Xinshe Li ◽

James B. Lok ◽

...

Keyword(s):

Signaling Pathway ◽

Nuclear Receptor ◽

Transcriptional Activity ◽

Strongyloides Stercoralis ◽

Parasite Development ◽

Binding Motif ◽

Nuclear Receptor Coactivator ◽

Interacting Protein ◽

Third Stage ◽

Infectious Stage

DAF-12 is nematode-specific nuclear receptor that has been proposed to govern development of the infectious stage of parasitic species, including Strongyloides stercoralis. Here, we identified a parasite-specific coactivator, called DAF-12 interacting protein-1 (DIP-1), that is required for DAF-12 ligand-dependent transcriptional activity. DIP-1 is found only in Strongyloides spp. and selectively interacts with DAF-12 through an atypical receptor binding motif. Using CRISPR/Cas9-directed mutagenesis, we demonstrate that DAF-12 is required for the requisite developmental arrest and the ligand-dependent reactivation of infectious S. stercoralis infective third-stage larvae, and that these effects require the DIP-1 coactivator. These studies reveal the existence of a distinct nuclear receptor/coactivator signaling pathway that governs parasite development.

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NCOA3 (nuclear receptor coactivator 3)

Atlas of Genetics and Cytogenetics in Oncology and Haematology ◽

10.4267/2042/38207 ◽

2011 ◽

Author(s):

SL Anzick

Keyword(s):

Nuclear Receptor ◽

Nuclear Receptor Coactivator

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Abstract 43: Activation of the Nuclear Receptor Coactivator PGC-1α Mediates an Atheroprotective Effect

Circulation Research ◽

10.1161/res.111.suppl_1.a43 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Cathal McCarthy ◽

Declan Mooney ◽

Monica de Gaetano ◽

William James ◽

Desmond J Fitzgerald ◽

...

Keyword(s):

Nuclear Receptor ◽

Target Genes ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Nuclear Receptor Coactivator ◽

Hub Gene ◽

Cd36 Expression ◽

Ppar Agonists ◽

Human Atherosclerosis

Supplementing dietary chow with conjugated linoleic acid (CLA) induces marked regression of pre-established murine atherosclerosis, in contrast to other PPAR agonists. The finding suggests that there are unidentified endogenous pathways that suppress the progression or promote the regression of atherosclerosis. Identifying these pathways in the mouse and their homologues in humans may help elucidate the mechanisms of the disease and targets for future therapies. Here, we provide evidence that CLA inhibits foam cell formation via regulation of the nuclear receptor co-activator, PGC-1α in a manner that differs from PPAR activation. Gene expression analysis was performed in the aorta of ApoE -/- mice following induction of atherosclerosis and dietary supplementation with/without CLA. CLA induced dramatic regression of the cholesterol-induced atherosclerosis. PGC-1α was identified as a ‘hub’ gene within a cluster of genes induced by CLA in the aorta of the ApoE -/- during regression. PGC-1α protein was also found in murine and human atherosclerotic plaque, where it was localised to macrophage/foam cells. In a mouse macrophage cell line exposed to oxLDL, CLA induced PGC-1α and several genes in the network in an isomer specific fashion, including RORαand ABCA1. CLA also induced the PGC-1α target genes Cyp7b1 and UCP-1, and PPAR. CLA inhibited foam cell formation in the same cells exposed to oxLDL and suppressed the expression of the scavenger receptors, SRA-1 and CD36. Expression of the PGC-1α in macrophages had similar effects. Thus, over-expression of PGC-1α limited the accumulation of oxLDL and subsequent foam cell formation, while deletion of the gene promoted foam cell formation in bone marrow derived macrophages upon exposure to oxLDL. Moreover, deletion of PGC-1α prevented the inhibition of macrophages/foam cell formation by CLA. The nuclear receptor co-activator PGC-1α is a hub gene in a network of genes activated in the aorta during CLA-induced regression of atherosclerosis and mediates CLA’s inhibition of foam cell formation. PGC-1α is also is also expressed in human plaques where its expression is inversely associated with disease progression, raising the possibility that this pathway if activated could regulate human atherosclerosis.

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