Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor

Sasa Vukelic, Olivera Stojadinovic, Irena Pastar, Constantinos Vouthounis, Agata Krzyzanowska, Sharmistha Das, Herbert H. Samuels, Marjana Tomic-Canic

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 acidA (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.

Original languageEnglish
Pages (from-to)1980-1988
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number3
DOIs
StatePublished - Jan 15 2010

Fingerprint

Glucocorticoid Receptors
Wound Healing
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Keratinocytes
Geranyltranstransferase
farnesyl pyrophosphate
Farnesyl-Diphosphate Farnesyltransferase
Keratin-6
Protein Prenylation
Chemical activation
Prenylation
Hydroxymethylglutaryl CoA Reductases
Mevalonic Acid
Cytoplasmic and Nuclear Receptors
Glucocorticoids
Cell culture
Culture Media
Cell Culture Techniques
Skin
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor. / Vukelic, Sasa; Stojadinovic, Olivera; Pastar, Irena; Vouthounis, Constantinos; Krzyzanowska, Agata; Das, Sharmistha; Samuels, Herbert H.; Tomic-Canic, Marjana.

In: Journal of Biological Chemistry, Vol. 285, No. 3, 15.01.2010, p. 1980-1988.

Research output: Contribution to journalArticle

Vukelic, Sasa ; Stojadinovic, Olivera ; Pastar, Irena ; Vouthounis, Constantinos ; Krzyzanowska, Agata ; Das, Sharmistha ; Samuels, Herbert H. ; Tomic-Canic, Marjana. / Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 3. pp. 1980-1988.
@article{7e9be8b105f64275a98942de82d1f3ae,
title = "Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor",
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 acidA (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.",
author = "Sasa Vukelic and Olivera Stojadinovic and Irena Pastar and Constantinos Vouthounis and Agata Krzyzanowska and Sharmistha Das and Samuels, {Herbert H.} and Marjana Tomic-Canic",
year = "2010",
month = "1",
day = "15",
doi = "10.1074/jbc.M109.016741",
language = "English",
volume = "285",
pages = "1980--1988",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "3",

}

TY - JOUR

T1 - Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor

AU - Vukelic, Sasa

AU - Stojadinovic, Olivera

AU - Pastar, Irena

AU - Vouthounis, Constantinos

AU - Krzyzanowska, Agata

AU - Das, Sharmistha

AU - Samuels, Herbert H.

AU - Tomic-Canic, Marjana

PY - 2010/1/15

Y1 - 2010/1/15

N2 - 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 acidA (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.

AB - 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 acidA (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.

UR - http://www.scopus.com/inward/record.url?scp=76249083086&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76249083086&partnerID=8YFLogxK

U2 - 10.1074/jbc.M109.016741

DO - 10.1074/jbc.M109.016741

M3 - Article

VL - 285

SP - 1980

EP - 1988

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 3

ER -