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J. Biol. Chem. 285 (3): 1980-1988

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Farnesyl Pyrophosphate Inhibits Epithelialization and Wound Healing through the Glucocorticoid Receptor*

Sasa Vukelic{ddagger}, Olivera Stojadinovic§, Irena Pastar§, Constantinos Vouthounis{ddagger}, Agata Krzyzanowska{ddagger}, Sharmistha Das, Herbert H. Samuels, , and Marjana Tomic-Canic{ddagger}§1

From the {ddagger}Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York, New York 10021,
the §Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, and
the Department of Pharmacology, New York University School of Medicine, New York, New York 10016

ABSTRACT Back to Top

Abstract: Farnesyl pyrophosphate (FPP), a key intermediate in the mevalonate pathway and protein farnesylation, can act as an agonist for several nuclear hormone receptors. Here we show a novel mechanism by which FPP inhibits wound healing acting as an agonist for glucocorticoid receptor (GR). Elevation of endogenous FPP by the squalene synthetase inhibitor zaragozic acid A (ZGA) or addition of FPP to the cell culture medium results in activation and nuclear translocation of the GR, a known wound healing inhibitor. We used functional studies to evaluate the effects of FPP on wound healing. Both FPP and ZGA inhibited keratinocyte migration and epithelialization in vitro and ex vivo. These effects were independent of farnesylation and indicate that modulation of FPP levels in skin may be beneficial for wound healing. FPP inhibition of keratinocyte migration and wound healing proceeds, in part, by repression of the keratin 6 gene. Furthermore, we show that the 3-hydroxy-3-methylglutaryl-CoA-reductase inhibitor mevastatin, which blocks FPP formation, not only promotes epithelialization in acute wounds but also reverses the effect of ZGA on activation of the GR and inhibition of epithelialization. We conclude that FPP inhibits wound healing by acting as a GR agonist. Of special interest is that FPP is naturally present in cells prior to glucocorticoid synthesis and that FPP levels can be further altered by the statins. Therefore, our findings may provide a better understanding of the pleiotropic effects of statins as well as molecular mechanisms by which they may accelerate wound healing.


Key Words: Cell/Epithelial • Diseases • Hormones/Steroid • Lipid/Cholesterol • Receptors/Steroid/Thyroid • Tissue/Organ Systems/Skin • Statins • Wound Healing

Received for publication May 4, 2009. Revision received October 26, 2009.

1 To whom correspondence should be addressed: 1600 N.W. 10th Ave., RMSB, Rm. 2023-A, Miami, FL 33136. Fax: 305-243-6191; E-mail: mtcanic{at}med.miami.edu.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Induction of Specific MicroRNAs Inhibits Cutaneous Wound Healing.
I. Pastar, A. A. Khan, O. Stojadinovic, E. A. Lebrun, M. C. Medina, H. Brem, R. S. Kirsner, J. J. Jimenez, C. Leslie, and M. Tomic-Canic (2012)
J. Biol. Chem. 287, 29324-29335
   Abstract »    Full Text »    PDF »
Nuclear receptor engineering based on novel structure activity relationships revealed by farnesyl pyrophosphate.
R. Goyanka, S. Das, H. H. Samuels, and T. Cardozo (2010)
Protein Eng. Des. Sel. 23, 809-815
   Abstract »    Full Text »    PDF »

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