Farnesyl pyrophosphate is a novel transcriptional activator for a subset of nuclear hormone receptors.

In silico docking of a chemical library with the ligand-binding domain of thyroid hormone nuclear receptor-beta (TRbeta) suggested that farnesyl pyrophosphate (FPP), a key intermediate in cholesterol synthesis and protein farnesylation, might function as an agonist. Surprisingly, addition of FPP to cells activated TR as well as the classical steroid hormone receptors but not peroxisome proliferative-activating receptors, farnesoid X receptor, liver X receptor, or several orphan nuclear receptors the ligands of which are unknown. FPP enhanced receptor-coactivator binding in vitro and in vivo, and elevation of FPP levels in cells by squalene synthetase or farnesyl transferase inhibitors leads to activation. The FPP effect was blocked by selective receptor antagonists, and in silico docking with 143 nuclear receptor ligand-binding domain structures revealed that FPP only docked with the agonist conformation of those receptors activated by FPP. Our results suggest that certain nuclear receptors maintain a common structural feature that may reflect an action of FPP on an ancient nuclear receptor or that FPP could function as a ligand for one of the many orphan nuclear receptors the ligands of which have not yet been identified. This finding also has potential interesting implications that may, in part, explain the pleotropic effects of statins as well as certain actions of farnesylation inhibitors in cells.

[1]  C. Hänni,et al.  Ligand binding was acquired during evolution of nuclear receptors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Ping Wei,et al.  Regulation of PPARγ coactivator 1α (PGC-1α) signaling by an estrogen-related receptor α (ERRα) ligand , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Á. Pascual,et al.  Nuclear hormone receptors and gene expression. , 2001, Physiological reviews.

[4]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[5]  Vincent Laudet,et al.  International Union of Pharmacology. LXVI. Orphan Nuclear Receptors , 2006, Pharmacological Reviews.

[6]  M. Davidson.  Squalene synthase inhibition: A novel target for the management of dyslipidemia , 2007, Current atherosclerosis reports.

[7]  R. Hohl,et al.  Simultaneous determination of farnesyl and geranylgeranyl pyrophosphate levels in cultured cells. , 2005, Analytical biochemistry.

[8]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Moore,et al.  , Margarita for Repression MechanismsReceptor Transactivation : Two XHepatocyte Nuclear Factor 4 and Retinoid The Orphan Nuclear Receptor SHP Inhibits , 1999 .

[10]  Grace Jones,et al.  The retinoid‐X receptor ortholog, ultraspiracle, binds with nanomolar affinity to an endogenous morphogenetic ligand , 2006, The FEBS journal.

[11]  V. Laudet,et al.  The evolution of the nuclear receptor superfamily. , 2004, Essays in biochemistry.

[12]  Kelvin K. W. Chan,et al.  The statins as anticancer agents. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  Timothy M Willson,et al.  Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids. , 2002, Structure.

[14]  M. Milburn,et al.  The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Janet Hager,et al.  Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP , 2005, Nature Structural &Molecular Biology.

[16]  D. J. Heard,et al.  Human ERRgamma, a third member of the estrogen receptor-related receptor (ERR) subfamily of orphan nuclear receptors: tissue-specific isoforms are expressed during development and in the adult. , 2000, Molecular endocrinology.

[17]  Jean-Paul Renaud,et al.  All-trans retinoic acid is a ligand for the orphan nuclear receptor RORβ , 2003, Nature Structural Biology.

[18]  M. Redinbo,et al.  Orphan nuclear receptors adopted by crystallography. , 2005, Current opinion in structural biology.

[19]  K. Umesono,et al.  LXXLL-Related Motifs in Dax-1 Have Target Specificity for the Orphan Nuclear Receptors Ad4BP/SF-1 and LRH-1 , 2003, Molecular and Cellular Biology.

[20]  Vincent Laudet,et al.  Principles for modulation of the nuclear receptor superfamily , 2004, Nature Reviews Drug Discovery.

[21]  Jasmine Chen,et al.  Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. , 1999, Molecular cell.

[22]  S. Kliewer,et al.  Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. , 2005, Molecular cell.

[23]  V. Craig Jordan,et al.  International Union of Pharmacology. LXIV. Estrogen Receptors , 2006, Pharmacological Reviews.

[24]  W. Pratt,et al.  Animal and plant cell lysates share a conserved chaperone system that assembles the glucocorticoid receptor into a functional heterocomplex with hsp90. , 1996, Biochemistry.

[25]  R Abagyan,et al.  High-throughput docking for lead generation. , 2001, Current opinion in chemical biology.

[26]  Donald P. McDonnell,et al.  International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors , 2006, Pharmacological Reviews.

[27]  G. Eichele,et al.  International Union of Pharmacology. LX. Retinoic Acid Receptors , 2006, Pharmacological Reviews.

[28]  S. Shoelson,et al.  Crystal Structure of the HNF4α Ligand Binding Domain in Complex with Endogenous Fatty Acid Ligand* , 2002, The Journal of Biological Chemistry.

[29]  H. Samuels,et al.  NRC-Interacting Factor 1 Is a Novel Cotransducer That Interacts with and Regulates the Activity of the Nuclear Hormone Receptor Coactivator NRC , 2002, Molecular and Cellular Biology.

[30]  Yong Xu,et al.  Activation of transcription through the ligand-binding pocket of the orphan nuclear receptor ultraspiracle. , 2002, European journal of biochemistry.

[31]  J. Collins,et al.  Human Glucocorticoid Receptor β Binds RU-486 and Is TranscriptionallyActive , 2007, Molecular and Cellular Biology.

[32]  Shen-Liang Chen,et al.  Characterization of the Retinoid Orphan-Related Receptor-Coactivator Binding Interface : A Structural Basis for Ligand-Independent Transcription , 2002 .

[33]  M. Piulachs,et al.  The mevalonate pathway and the synthesis of juvenile hormone in insects. , 2005, Annual review of entomology.

[34]  L. Gilbert,et al.  Transcriptional activation of the Drosophila ecdysone receptor by insect and plant ecdysteroids. , 2000, Insect biochemistry and molecular biology.

[35]  S. Perrey,et al.  Embryonic Lethality and Defective Neural Tube Closure in Mice Lacking Squalene Synthase* , 1999, The Journal of Biological Chemistry.

[36]  R. Abagyan,et al.  Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. , 1994, Journal of molecular biology.

[37]  T. Willson,et al.  Structural Analyses Reveal Phosphatidyl Inositols as Ligands for the NR5 Orphan Receptors SF-1 and LRH-1 , 2005, Cell.

[38]  Darrell R. Abernethy,et al.  International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels , 2003, Pharmacological Reviews.

[39]  Bert W O'Malley,et al.  Coregulator function: a key to understanding tissue specificity of selective receptor modulators. , 2004, Endocrine reviews.

[40]  C. Steele,et al.  An in vivo/in vitro evaluation of the teratogenic action of excess vitamin A. , 1983, Teratology.

[41]  Ruben Abagyan,et al.  Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[42]  S. Kliewer,et al.  Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[43]  H. Samuels,et al.  Nuclear hormone receptor coregulator: role in hormone action, metabolism, growth, and development. , 2005, Endocrine reviews.

[44]  J. W. Thornton,et al.  The Octopus vulgaris estrogen receptor is a constitutive transcriptional activator: evolutionary and functional implications. , 2006, Endocrinology.

[45]  David Crews,et al.  Resurrecting the Ancestral Steroid Receptor: Ancient Origin of Estrogen Signaling , 2003, Science.

[46]  B. Spiegelman,et al.  International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors , 2006, Pharmacological Reviews.

[47]  G. Prendergast,et al.  Farnesyltransferase inhibitors: antineoplastic properties, mechanisms of action, and clinical prospects. , 2000, Seminars in cancer biology.

[48]  R. Keller,et al.  Squalene synthase inhibition alters metabolism of nonsterols in rat liver. , 1996, Biochimica et biophysica acta.

[49]  B. Raaka,et al.  Role of the conserved C-terminal region of thyroid hormone receptor-α in ligand-dependent transcriptional activation , 1998, Molecular and Cellular Endocrinology.

[50]  R Abagyan,et al.  Homology modeling by the ICM method , 1995, Proteins.

[51]  R. Evans,et al.  The structure of the ultraspiracle ligand-binding domain reveals a nuclear receptor locked in an inactive conformation. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[52]  T. Nishimoto,et al.  Lipid-lowering effects of TAK-475, a squalene synthase inhibitor, in animal models of familial hypercholesterolemia. , 2003, European journal of pharmacology.

[53]  J. Carroll,et al.  Contrasting effects of prenyltransferase inhibitors on estrogen-dependent cell cycle progression and estrogen receptor-mediated transcriptional activity in MCF-7 cells. , 2003, Endocrinology.

[54]  D. Moras,et al.  Crystal Structure of the Ligand-binding Domain of the Ultraspiracle Protein USP, the Ortholog of Retinoid X Receptors in Insects* , 2001, The Journal of Biological Chemistry.

[55]  H. Gronemeyer,et al.  Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications. , 2000, Trends in pharmacological sciences.

[56]  Claudio N. Cavasotto,et al.  Structure‐based identification of binding sites, native ligands and potential inhibitors for G‐protein coupled receptors , 2003, Proteins.

[57]  Ruben Abagyan,et al.  Nuclear hormone receptor targeted virtual screening. , 2003, Journal of medicinal chemistry.

[58]  Wen Xie,et al.  International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor α, Farnesoid X Receptor β, Liver X Receptor α, Liver X Receptor β, and Vitamin D Receptor , 2006, Pharmacological Reviews.

[59]  C. Napoli,et al.  Statin effects beyond lipid lowering--are they clinically relevant? , 2003, European heart journal.

[60]  A. Steinmetz,et al.  X‐ray structure of the orphan nuclear receptor RORβ ligand‐binding domain in the active conformation , 2001, The EMBO journal.

[61]  H. Samuels,et al.  A New Family of Nuclear Receptor Coregulators That Integrate Nuclear Receptor Signaling through CREB-Binding Protein , 2000, Molecular and Cellular Biology.

[62]  Gregor Eichele,et al.  International Union of Pharmacology. LXIII. Retinoid X Receptors , 2006, Pharmacological Reviews.

[63]  Claudio N. Cavasotto,et al.  In silico identification of novel EGFR inhibitors with antiproliferative activity against cancer cells. , 2006, Bioorganic & medicinal chemistry letters.

[64]  P. Chambon,et al.  Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. , 2000, Molecular cell.

[65]  Samuel Refetoff,et al.  International Union of Pharmacology. LIX. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Thyroid Hormone Receptors , 2006, Pharmacological Reviews.

[66]  Ruben Abagyan,et al.  In silico discovery of novel Retinoic Acid Receptor agonist structures , 2001, BMC Structural Biology.

[67]  R Abagyan,et al.  Rational discovery of novel nuclear hormone receptor antagonists , 2000, Proc. Natl. Acad. Sci. USA.

[68]  T. A. Kerr,et al.  Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. , 2000, Molecular cell.

[69]  G. Rodan,et al.  Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. , 2000, Archives of biochemistry and biophysics.

[70]  T. Perlmann,et al.  Digging deep into the pockets of orphan nuclear receptors: insights from structural studies. , 2004, Trends in cell biology.