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

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