Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP

Ortlund, Eric A.; Lee, Yoon‐Kwang; Solomon, Isaac H.; Hager, Janet; Safi, Rachid; Choi, Yunhee; Guan, Ziqiang; Tripathy, Ashutosh; Raetz, Christian R. H.; McDonnell, Donald P.; Moore, David D.; Redinbo, Matthew R.

doi:10.1038/nsmb910

Cited by 192 publications

(231 citation statements)

References 47 publications

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“…No evidence of alterations in the LRH-1 gene copy number was found in independent comparative genomic hybridization (CGH) studies using pancreatic cancer cells cultured in vitro (30). Our data showed decreased levels of Prox1 and SHP, two established corepressors of LRH-1 (3,11,16), in the majority of tested pancreatic cancer cell lines (Fig. S1 C and D), suggesting that changes in regulation of transcriptional activity of LRH-1 might be associated with pancreatic oncogenesis.…”

Section: Discussionmentioning

confidence: 58%

“…S1C). We also found the transcripts for SHP, another corepressor of LRH-1 (3,11), diminished in seven cancer cell lines tested (Fig. S1D).…”

Section: Identification Of Lrh-1 In Pancreatic Cancer Cells Cultured mentioning

confidence: 66%

“…LRH-1 is classed as an orphan nuclear receptor because its activating hormones have not been identified. Crystallographic and biochemical studies presented compelling evidence that LRH-1 could bind ligands (10)(11)(12)(13) and suggested phosphatidyl inositols as potential hormone candidates for this receptor (10). LRH-1 is also regulated via posttranslational modifications, phosphorylation, and sumoylation (14,15).…”

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confidence: 99%

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Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

Benod

Vinogradova

Jouravel

et al. 2011

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

116

125

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An essential regulator of gene transcription, nuclear receptor liver receptor homologue 1 (LRH-1) controls cell differentiation in the developing pancreas and maintains cholesterol homeostasis in adults. Recent genome-wide association studies linked mutations in the LRH-1 gene and its up-stream regulatory regions to development of pancreatic cancer. In this work, we show that LRH-1 transcription is activated up to 30-fold in human pancreatic cancer cells compared to normal pancreatic ductal epithelium. This activation correlates with markedly increased LRH-1 protein expression in human pancreatic ductal adenocarcinomas in vivo. Selective blocking of LRH-1 by receptor specific siRNA significantly inhibits pancreatic cancer cell proliferation in vitro. The inhibition is tracked in part to the attenuation of the receptor's transcriptional targets controlling cell growth, proliferation, and differentiation. Previously, LRH-1 was shown to contribute to formation of intestinal tumors. This study demonstrates the critical involvement of LRH-1 in development and progression of pancreatic cancer, suggesting the LRH-1 receptor as a plausible therapeutic target for treatment of pancreatic ductal adenocarcinomas.protein target | gene regulation W ith mortality rate nearing its incidence, pancreatic ductal adenocarcinoma (PDAC) presents a challenge for modern oncology. Current chemotherapy drugs approved for pancreatic cancer are not organ specific and are modestly effective. Thus, there is a need for improved therapeutic options and effective pancreatic cancer drugs. Recent studies reveal that signaling pathways are similar in pancreatic development and malignant growth in the adult pancreas (1, 2). One of the common driving factors in pancreatic embryo-and oncogenesis is the nuclear receptor liver receptor homologue 1 (LRH-1,

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Section: Discussionmentioning

confidence: 58%

“…S1C). We also found the transcripts for SHP, another corepressor of LRH-1 (3,11), diminished in seven cancer cell lines tested (Fig. S1D).…”

Section: Identification Of Lrh-1 In Pancreatic Cancer Cells Cultured mentioning

confidence: 66%

mentioning

confidence: 99%

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Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

Benod

Vinogradova

Jouravel

et al. 2011

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

116

125

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“…Previously recognized as an orphan receptor, phospholipids, including the phosphatidyl inositol second messengers, have been proposed as ligands for the human form (2)(3)(4). Although the role of LRH-1 in cholesterol and bile acid homeostasis is relatively well established (5)(6)(7)(8)(9)(10)(11)(12)(13)(14), unanticipated actions of LRH-1 in the intestine have emerged, including control of cell renewal (15).…”

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confidence: 99%

LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

Coste

Dubuquoy

Barnouin

et al. 2007

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

139

205

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Liver receptor homolog-1 (LRH-1) is a nuclear receptor involved in intestinal lipid homeostasis and cell proliferation. Here we show that haploinsufficiency of LRH-1 predisposes mice to the development of intestinal inflammation. Besides the increased inflammatory response, LRH-1 heterozygous mice exposed to 2,4,6-trinitrobenzene sulfonic acid show lower local corticosterone production as a result of an impaired intestinal expression of the enzymes CYP11A1 and CYP11B1, which control the local synthesis of corticosterone in the intestine. Local glucocorticoid production is strictly enterocytedependent because it is robustly reduced in epithelium-specific LRH-1-deficient mice. Consistent with these findings, colon biopsies of patients with Crohn's disease and ulcerative colitis show reduced expression of LRH-1 and genes involved in the production of glucocorticoids. Hence, LRH-1 regulates intestinal immunity in response to immunological stress by triggering local glucocorticoid production. These findings underscore the importance of LRH-1 in the control of intestinal inflammation and the pathogenesis of inflammatory bowel disease.Crohn's disease ͉ inflammation ͉ nuclear receptors ͉ steroidogenesis ͉ ulcerative colitis

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“…Compounds modulating the activity of LRH-1 could represent an attractive new therapy for multiple indications because LRH-1 has been implicated in the inflammatory response, tumour formation, bile acid homeostasis and fertility (Botrugno et al 2004;Schoonjans et al 2005;Mueller et al 2006;Venteclef et al 2006Venteclef et al , 2011Coste et al 2007;Mataki et al 2007;Duggavathi et al 2008;Lee et al 2008;Out et al 2011). The crystal structure of LRH-1 in complex with cofactor peptides reveals the presence of phospholipids in the ligand-binding domain, indicating that the activity of LRH-1 can potentially be modulated (Ortlund et al 2005;Burendahl et al 2008). This was further delineated by the description of LRH-1 agonists by Whitby et al (2006Whitby et al ( , 2011.…”

Section: Introductionmentioning

confidence: 99%

Reversible infertility in a liver receptor homologue-1 (LRH-1)-knockdown mouse model

Gerrits

Paradé

Koonen-Reemst

et al. 2014

Reprod. Fertil. Dev.

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Abstract. Liver receptor homologue-1 (LRH-1) is an orphan nuclear receptor that has been implicated in steroid hormone biosynthesis and fertility. Herein we describe a transgenic inducible short hairpin (sh) RNA mouse model that was used to study the effect of transient LRH-1 knockdown in vivo. Induction of expression of the shRNA directed against LRH-1 for 2-6 weeks resulted in 80% knockdown of LRH-1 protein in the ovary and complete infertility. Gonadotropin hyperstimulation could not rescue the observed defects in ovulation and corpus luteum formation in LRH-1-knockdown mice. The infertility phenotype was fully reversible because LRH-1-knockdown females became pregnant and delivered normal size litters and healthy pups after cessation of LRH-1 shRNA expression. Timed ovarian microarray analysis showed that, in line with the observed decrease in plasma progesterone levels, key steroid biosynthesis genes, namely Star, Cyp11a1, Hsd3b and Scarb1, were downregulated in LRH-1-knockdown ovaries. In contrast with what has been described previously, no clear effect was observed on oestrogenic activity in LRH-1-knockdown mice. Only Sult1e1 and, surprisingly, Hsd17b7 expression was modulated with potentially opposite effects on oestradiol bioavailability. In conclusion, the fully reversible infertility phenotype of LRH-1-knockdown mice shows the feasibility of an LRH-1 antagonist as new contraceptive therapy with a mechanism of action that most prominently affects cholesterol availability and progesterone production.

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Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP

Cited by 192 publications

References 47 publications

Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

Reversible infertility in a liver receptor homologue-1 (LRH-1)-knockdown mouse model

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