help button home button Endocrine Society Molecular Endocrinology ENDO 08 Sessions Library
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

Molecular Endocrinology, doi:10.1210/me.2007-0080
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow NURSA Molecule Pages Link
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Das, S.
Right arrow Articles by Samuels, H. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Das, S.
Right arrow Articles by Samuels, H. H.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Molecular Endocrinology 21 (11): 2672-2686
Copyright © 2007 by The Endocrine Society

Farnesyl Pyrophosphate Is a Novel Transcriptional Activator for a Subset of Nuclear Hormone Receptors

Sharmistha Das, Matthieu Schapira, Marjana Tomic-Canic, Ritu Goyanka, Timothy Cardozo and Herbert H. Samuels

Department of Pharmacology (S.D., R.G., T.C., H.H.S.), New York University School of Medicine, New York, New York 10016; Structural Genomics Consortium (M.S.), Banting Building, University of Toronto, Toronto, Ontario, Canada M5G 1L5; and Department of Dermatology (M.T.-C.), Weill Medical College of the Cornell University, New York, New York 10021

Address all correspondence and requests for reprints to: Herbert Samuels, Departments of Pharmacology and Medicine, New York University School of Medicine, 550 First Avenue, Room MSB-424, New York, New York 10016. E-mail: herbert.samuels{at}med.nyu.edu.

In silico docking of a chemical library with the ligand-binding domain of thyroid hormone nuclear receptor-ß (TRß) 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  RARα  |  LXRα  |  FXRα  |  VDR  |  RXRα  |  ERα  |  GR
Coregulators:   ASC-2
Ligands:   all-trans-Retinoic acid  |  Calcitriol  |  Dexamethasone  |  17β-Estradiol  |  9-cis-Retinoic acid  |  Thyroid hormone  |  Mifepristone  |  Rosiglitazone  |  Fulvestrant



This article has been cited by other articles:


Home page
Cancer Res.Home page
A. A. Tinnikov, K. T. Yeung, S. Das, and H. H. Samuels
Identification of a Novel Pathway That Selectively Modulates Apoptosis of Breast Cancer Cells
Cancer Res., February 15, 2009; 69(4): 1375 - 1382.
[Abstract] [Full Text] [PDF]


Home page
Physiol. Rev.Home page
P. Lefebvre, B. Cariou, F. Lien, F. Kuipers, and B. Staels
Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation
Physiol Rev, January 1, 2009; 89(1): 147 - 191.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
D. Y. Oh, J. M. Yoon, M. J. Moon, J.-I. Hwang, H. Choe, J. Y. Lee, J. I. Kim, S. Kim, H. Rhim, D. K. O'Dell, et al.
Identification of Farnesyl Pyrophosphate and N-Arachidonylglycine as Endogenous Ligands for GPR92
J. Biol. Chem., July 25, 2008; 283(30): 21054 - 21064.
[Abstract] [Full Text] [PDF]




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2007 by The Endocrine Society