Structural Analyses Reveal Phosphatidyl Inositols as Ligands for the NR5 Orphan Receptors SF-1 and LRH-1

Krylova, I. N.; Sablin, Elena P.; Moore, Jamie; Xu, Renfeng; Waitt, Greg; MacKay, J. Andrew; Juzumiene, Dalia; Bynum, Jane; Madauss, Kevin P.; Montana, V.G.; Lebedeva, Lioudmila A.; Suzawa, Miyuki; Williams, Jon D.; Williams, Shawn P.; Guy, R. Kiplin; Thornton, Joseph W.; Fletterick, Robert J.; Willson, Timothy M.; Ingraham, Holly A.

doi:10.1016/j.cell.2005.01.024

Cited by 375 publications

(399 citation statements)

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“…This hypothesis is supported by studies using the scintillation proximity assay in which we demonstrated that SF1 binds to various phospholipids and sphingolipids, including PE, phosphatidylcholine (PC), phosphatidic acid (PA), PIPs, and S1P. Various mixtures of PE, PA, and PIPs were identified as ligands in crystallographic studies (Krylova et al, 2005;Li et al, 2005;Wang et al, 2005), further supporting a potential role for multiple phospholipids and sphingolipids in regulating SF1 function. …”

mentioning

confidence: 59%

Section: Regulation Of Sf1 Activitymentioning

confidence: 99%

“…However, subsequent crystallographic studies carried out by three laboratories have shown that phospholipids are ligands for SF1 (Ingraham and Redinbo, 2005;Krylova et al, 2005;Li et al, 2005;Wang et al, 2005). The interaction of phosphatidylinositol phosphates (PIPs) with the LBD of murine SF1 has been shown to be required for maximal activity of the receptor (Krylova et al, 2005). Li et al found that the receptor has a large LBD (approximately 1600 Å) that interacts with phospholipids that have fatty acid side chains between twelve and eighteen carbons and thus inferred that SF1 may readily exchange its ligands to respond to different phospholipid species (Li et al, 2005).…”

Section: Regulation Of Sf1 Activitymentioning

confidence: 99%

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Steroidogenic factor-1 is a sphingolipid binding protein

Urs

Dammer

Kelly

et al. 2007

Molecular and Cellular Endocrinology

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Steroidogenic factor (SF1, NR5A1, Ad4BP) is an orphan nuclear receptor that is essential for steroid hormone-biosynthesis and endocrine development. Studies have found that the ability of this receptor to increase target gene expression can be regulated by post-translational modification, subnuclear localization, and protein-protein interactions. Recent crystallographic studies and our mass spectrometric analyses of the endogenous receptor have demonstrated an integral role for ligandbinding in the control of SF1 transactivation activity. Herein, we discuss our findings that sphingosine is an endogenous ligand for SF1. These studies and the structural findings of others have demonstrated that the receptor can bind both sphingolipids and phospholipids. Thus, it is likely that multiple bioactive lipids are ligands for SF1 and that these lipids will differentially act to control SF1 activity in a context-dependent manner. Finally, these findings highlight a central role for bioactive lipids as mediators of trophic-hormone stimulated steroid hormone biosynthesis. Keywordssteroidogenic factor-1; CYP17; sphingosine; cAMP; adrenocorticotropin Regulation of SF1 activitySteroid hormone biosynthesis involves the concerted action of a group of proteins that regulate substrate delivery and metabolism. Both the activity and expression of these enzymes is controlled by the integration of signaling pathways. One of these signal transduction pathways involves the activation of the cAMP-dependent protein kinase (PKA). A consequence of PKA activation is increased transcription of steroidogenic genes. This increase in transcription is mediated by the binding of various transcription factors, including SF1, to cAMP responsive sequences in the promoters of steroidogenic genes (Sewer and Waterman, 2001;Sewer and Waterman, 2003). SF1 is a nuclear receptor that plays a key role not only in steroidogenesis (Bakke et al., 2001), but also in endocrine development and sex differentiation (Hammer et al., 2005;Parker et al., 2002).Many laboratories have carried out research to determine the mechanism by which SF1 activates steroidogenic gene transcription. Although transcription of steroidogenic genes Corresponding author: Marion B. Sewer, School of Biology, Georgia Institute of Technology, 310 Ferst Drive, Atlanta, Tel: (404) Fax: (404) 894-0519; E-mail: marion.sewer@biology.gatech.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Bioactive sphingolipids in steroidogenesisSphingolipids are a diverse family of amphiphatic molecules that are comprised of a long-chain ...

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confidence: 59%

Section: Regulation Of Sf1 Activitymentioning

confidence: 99%

Section: Regulation Of Sf1 Activitymentioning

confidence: 99%

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Steroidogenic factor-1 is a sphingolipid binding protein

Urs

Dammer

Kelly

et al. 2007

Molecular and Cellular Endocrinology

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“…Although our understanding of the role of nuclear phosphoinositides is limited (Lian and Di Cristofano, 2005;Neri et al, 2002), recent studies confirm the presence of PI3K, PDK1, Akt and Pten in the nucleus (Lian and Di Cristofano, 2005). Additional work has revealed that the activity of steroidogenic factor-1 and liver receptor homolog 1, two members of the nuclear receptor superfamily of transcription factors thought to exhibit ligand-independent activity, is regulated by binding phosphatidylinositol-3,4,5 trisphoshosphate (Krylova et al, 2005). Thus, accumulation of nuclear PIP3 in response to estrogen-mediated activation of ERα and/or GPR30 may regulate gene expression through this family of nuclear receptors.…”

Section: Gpr30-mediated Signalingmentioning

confidence: 99%

GPR30: A G protein-coupled receptor for estrogen

Prossnitz

Arterburn

Sklar

2007

Molecular and Cellular Endocrinology

268

184

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Estrogen is a critical steroid in human physiology exerting its effect both at the transcriptional level as well as at the level of rapid intracellular signaling through second messengers. Many of estrogen's transcriptional effects have long been known to be mediated through classical nuclear steroid receptors but recent studies also demonstrate the existence of a 7-transmembrane G protein-coupled receptor, GPR30 that responds to estrogen with rapid cellular signaling. There is currently controversy over the ability of classical estrogen receptors to recapitulate GPR30-mediated signaling mechanisms and vice versa. This article will summarize recent literature and address the relationship between GPR30 and conventional estrogen receptor signaling.

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“…Recent findings demonstrate that LRH-1 has constitutive transcriptional activity by adopting an active conformation with a large but empty ligand pocket (Sablin et al, 2003), but also identify phosphatidyl inositols as ligands modulating LRH-1 transcriptional activity (Krylova et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene

et al. 2005

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Liver receptor homolog-1 (LRH-1) is a nuclear receptor previously known to have distinct functions during mouse development and essential roles in cholesterol homeostasis. Recently, a new role for LRH-1 has been discovered in tumor progression, giving LRH-1 potential transforming functions. In order to identify critical factors stimulating LRH-1 expression leading to deregulated cellular proliferation, we studied its expression and its regulation in several breast cancer cell lines. We observed that LRH-1 expression was increased in estrogen receptor (ER) a expressing cell lines, whereas weak-to-no expression was found in nonexpressing ERa cell lines. In MCF7, LRH-1 expression was highly induced after treatment with 17b-estradiol (E2). This transcriptional regulation was the result of a direct binding of the ER to the LRH-1 promoter, as demonstrated by gelshift and chromatin immunoprecipitation assays. Interestingly, siRNA-mediated inactivation of LRH-1 decreased the E2-dependent proliferation of MCF7 cells. Finally, LRH-1 protein expression was detected by immunohistochemistry in tumor cells of human mammary ductal carcinomas. Altogether, these data demonstrate that LRH-1 is transcriptionally regulated by the ER a and reinforce the hypothesis that LRH-1 could exert potential oncogenic effects during breast cancer formation.

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Structural Analyses Reveal Phosphatidyl Inositols as Ligands for the NR5 Orphan Receptors SF-1 and LRH-1

Cited by 375 publications

References 50 publications

Steroidogenic factor-1 is a sphingolipid binding protein

Steroidogenic factor-1 is a sphingolipid binding protein

GPR30: A G protein-coupled receptor for estrogen

The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene

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