Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)

Whitby, Richard J.; Stec, Józef; Blind, Raymond D.; Dixon, Sally; Leesnitzer, Lisa M.; Orband‐Miller, Lisa A.; Williams, Shawn P.; Willson, Timothy M.; Xu, Renfeng; Zuercher, William J.; Cai, Fang; Ingraham, Holly A.

doi:10.1021/jm1014296

Cited by 74 publications

(138 citation statements)

References 87 publications

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“…1A and Table S1). In comparison, affinity of RJW100 (20), a derivative of the synthetic NR5A ligand GSK8470 (21), was notably worse than PI(3,4,5)P 3 with an apparent K d of 1,200 ± 270 nM, as determined here by electrophoretic mobility-shift in native gels. We also noted that DLPC, a short-chained exogenous phosphatidylcholine LRH-1 ligand (16,22), binds SF-1 poorly.…”

Section: Significancementioning

confidence: 58%

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1

Blind¹,

Sablin

Kuchenbecker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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129

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The signaling phosphatidylinositol lipids PI(4,5)P 2 (PIP 2 ) and PI (3,4,5)P 3 (PIP 3 ) bind nuclear receptor 5A family (NR5As), but their regulatory mechanisms remain unknown. Here, the crystal structures of human NR5A1 (steroidogenic factor-1, SF-1) ligand binding domain (LBD) bound to PIP 2 and PIP 3 show the lipid hydrophobic tails sequestered in the hormone pocket, as predicted. However, unlike classic nuclear receptor hormones, the phosphoinositide head groups are fully solvent-exposed and complete the LBD fold by organizing the receptor architecture at the hormone pocket entrance. The highest affinity phosphoinositide ligand PIP 3 stabilizes the coactivator binding groove and increases coactivator peptide recruitment. This receptor-ligand topology defines a previously unidentified regulatory protein-lipid surface on SF-1 with the phosphoinositide head group at its nexus and poised to interact with other proteins. This surface on SF-1 coincides with the predicted binding site of the corepressor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X), and importantly harbors missense mutations associated with human endocrine disorders. Our data provide the structural basis for this poorly understood cluster of human SF-1 mutations and demonstrates how signaling phosphoinositides function as regulatory ligands for NR5As.T he existence of nuclear, nonmembrane pools of signaling phosphorylated derivatives of phosphatidylinositols or phosphoinositides (PIP n ) was reported over two decades ago (1-3). Consistent with these early reports, lipid-modifying enzymes responsible for phosphoinositide metabolism were also found in the nucleus (4-7); however, the function of PIP n in this cellular compartment remains poorly defined. The nuclear receptors (NRs) steroidogenic factor 1 (SF-1, NR5A1) and liver receptor homolog 1 (LRH-1, NR5A2) bind phosphoinositides as well as other phospholipids in their large hydrophobic pockets (8-13). The ability of NR5As to interact with PIP n is well-conserved with the Caenorhabditis elegans ortholog nhr-25 able to bind both PIP 2 and PIP 3 (14). That phosphoinositides might serve as endogenous NR5A ligands is suggested by the fact that elevating cellular pools of PIP 3 increases SF-1 activity (15) and that impairing PIP 3 uptake decreases SF-1 activity (12). Further, when purified from mammalian cells, the phosphoinositide PIP 2 is found associated with SF-1 and can be modified by the lipid kinase, IPMK, as well as the lipid phosphatase, PTEN (13). Taken together, these data suggest that signaling phosphoinositides are biologically relevant ligands for SF-1.Phosphoinositide ligands diverge chemically from classic NR hormones in that they contain a long, extended hydrophobic moiety and a prominent hydrophilic head group, which is inherently incompatible with the hydrophobic core of the NR5A ligand-binding pocket. Our previous structural analyses of SF-1 bound to phosphatidylcholine suggest that the acyl tails of phosphoinositides should be sequestered...

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Section: Significancementioning

confidence: 58%

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1

Blind¹,

Sablin

Kuchenbecker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

129

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“…Thus, LRH-1 plays an overarching role in regulating digestive processes. Since the transcriptional activity of LRH-1 can be modulated by small molecules (Whitby et al 2011), LRH-1 may serve as a pharmacologic target for treating diseases such as pancreatitis and cystic fibrosis that are associated with either the overproduction or underproduction of pancreatic enzymes.…”

Section: Resultsmentioning

confidence: 99%

LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function

Holmstrom¹,

Deering²,

Swift³

et al. 2011

Genes Dev.

112

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We have determined the cistrome and transcriptome for the nuclear receptor liver receptor homolog-1 (LRH-1) in exocrine pancreas. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq analyses reveal that LRH-1 directly induces expression of genes encoding digestive enzymes and secretory and mitochondrial proteins. LRH-1 cooperates with the pancreas transcription factor 1-L complex (PTF1-L) in regulating exocrine pancreas-specific gene expression. Elimination of LRH-1 in adult mice reduced the concentration of several lipases and proteases in pancreatic fluid and impaired pancreatic fluid secretion in response to cholecystokinin. Thus, LRH-1 is a key regulator of the exocrine pancreas-specific transcriptional network required for the production and secretion of pancreatic fluid.

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“…The structure of the hormone-binding domain of LRH-1 has been determined with four different phospholipids in the binding pocket (4)(5)(6).…”

mentioning

confidence: 99%

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Bayrer

Mukkamala

Sablin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Colorectal cancers (CRCs) account for nearly 10% of all cancer deaths in industrialized countries. Recent evidence points to a central role for the nuclear receptor liver receptor homolog-1 (LRH-1) in intestinal tumorigenesis. Interaction of LRH-1 with the Wnt/β-catenin pathway, highly active in a critical subpopulation of CRC cells, underscores the importance of elucidating LRH-1's role in this disease. Reduction of LRH-1 diminishes tumor burden in murine models of CRC; however, it is not known whether LRH-1 is required for tumorigenesis, for proliferation, or for both. In this work, we address this question through shRNA-mediated silencing of LRH-1 in established CRC cell lines. LRH-1 mRNA knockdown results in significantly impaired proliferation in a cell line highly expressing the receptor and more modest impairment in a cell line with moderate LRH-1 expression. Cell-cycle analysis shows prolongation of G0/G1 with LRH-1 silencing, consistent with LRH-1 cellcycle influences in other tissues. Cluster analysis of microarray gene expression demonstrates significant genome wide alterations with major effects in cell-cycle regulation, signal transduction, bile acid and cholesterol metabolism, and control of apoptosis. This study demonstrates a critical proproliferative role for LRH-1 in established colon cancer cell lines. LRH-1 exerts its effects via multiple signaling networks. Our results suggest that selected CRC patients could benefit from LRH-1 inhibitors.C olorectal cancer (CRC) accounts for nearly 10% of all cancer deaths in the United States. Much is understood about maintenance, but little is known about molecules driving initiation or metastasis of CRCs. Recent discoveries in animal and cellular models of CRC suggest a role for the nuclear receptor liver receptor homolog-1 (LRH-1, also known as NR5A2) (1).LRH-1, previously thought to be constitutively active, has a functional hormone-binding pocket that binds phosphatidylcholines (2, 3). The structure of the hormone-binding domain of LRH-1 has been determined with four different phospholipids in the binding pocket (4-6).LRH-1 is vital; knockout mouse embryos fail to undergo gastrulation (7). LRH-1 is expressed in the adult in the gastrointestinal tract, including liver and pancreas, and is also present in ovaries, where it regulates steroidogenesis (8). It is highly expressed in intestinal crypts where it is believed to play a role in intestinal epithelial cell renewal (9). LRH-1 has prominent roles in development, metabolism, stem-cell pluripotency, and tumorigenesis (10-14).LRH-1 figures prominently in WNT signaling in the intestine (9, 13). The WNT gene family is a large, conserved signaling pathway with roles in development, cellular homeostasis, and tumorigenesis (15). WNT signaling activates β-catenin, an important transcriptional coactivator that is active in over 80% of CRCs (16). LRH-1 physically binds to β-catenin and functions synergistically in the regulation of certain target genes, including cyclin E1 (9).LRH-1 and β-catenin contribute to ...

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Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)

Cited by 74 publications

References 87 publications

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1

LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

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Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)

Cited by 74 publications

References 87 publications

The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1

The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1

LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

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The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1