Crosstalk of Hypoxia-Mediated Signaling Pathways in Upregulating Plasminogen Activator Inhibitor-1 Expression in Keloid Fibroblasts

Qunzhou Zhang, Yidi Wu, Cindy H. Chau, David K. Ann, Charles Bertolami, Anh D. Le

Research output: Contribution to journalArticle

Abstract

Keloids are skin fibrotic conditions characterized by an excess accumulation of extracellular matrix (ECM) components secondary to trauma or surgical injuries. Previous studies have shown that plasminogen activator inhibitor-1 (PAI-1) can be upregulated by hypoxia and may contribute to keloid pathogenesis. In this study we investigate the signaling mechanisms involved in hypoxia-mediated PAI-1 expression in keloid fibroblasts. Using Northern and Western blot analysis, transient transfections, and pharmacological agents, we demonstrate that hypoxia-induced upregulation of PAI-1 expression is mainly controlled by hypoxia inducible factors-1α (HIF-1α) and that hypoxia leads to a rapid and transient activation of phosphatidylinositol-3-kinase/Akt (PI3-K/Akt) and extracellular signal-regulated kinases 1/2 (ERK1/2). Treatment of cells with PI-3K/Akt inhibitor (LY294002) and tyrosine protein kinase inhibitor (genistein) significantly attenuated hypoxia-induced PAI-1 mRNA and protein expression as well as promoter activation, apparently via an inhibition of the hypoxia-induced stabilization of HIF-1α protein, attenuation of the steady-state level of HIF-1α mRNA, and its DNA-binding activity. Even though disruption of ERK1/2 signaling pathway by PD98059 abolished hypoxia-induced PAI-1 promoter activation and mRNA/protein expression in keloid fibroblasts, it did not inhibit the hypoxia-mediated stabilization of HIF-1α protein and the steady-state level of HIF-1α mRNA nor its DNA binding activity. Our findings suggest that a combination of several signaling pathways, including ERK1/2, PI3-K/Akt, and protein tyrosine kinases (PTKs), may contribute to the hypoxia-mediated induction of PAI-1 expression via activation of HIF-1α in keloid fibroblasts.

Original languageEnglish (US)
Pages (from-to)89-97
Number of pages9
JournalJournal of Cellular Physiology
Volume199
Issue number1
DOIs
StatePublished - Apr 2004

Fingerprint

Keloid
Hypoxia-Inducible Factor 1
Plasminogen Activator Inhibitor 1
Fibroblasts
Crosstalk
Mitogen-Activated Protein Kinase 3
Chemical activation
Phosphatidylinositol 3-Kinase
Messenger RNA
Mitogen-Activated Protein Kinase 1
Protein-Tyrosine Kinases
Proteins
Stabilization
Genistein
DNA
Protein Kinase Inhibitors
Phosphatidylinositol 3-Kinases
Transient analysis
Hypoxia
Skin

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Crosstalk of Hypoxia-Mediated Signaling Pathways in Upregulating Plasminogen Activator Inhibitor-1 Expression in Keloid Fibroblasts. / Zhang, Qunzhou; Wu, Yidi; Chau, Cindy H.; Ann, David K.; Bertolami, Charles; Le, Anh D.

In: Journal of Cellular Physiology, Vol. 199, No. 1, 04.2004, p. 89-97.

Research output: Contribution to journalArticle

@article{836efe80e8ab45aeb0ff91a66543d26d,
title = "Crosstalk of Hypoxia-Mediated Signaling Pathways in Upregulating Plasminogen Activator Inhibitor-1 Expression in Keloid Fibroblasts",
abstract = "Keloids are skin fibrotic conditions characterized by an excess accumulation of extracellular matrix (ECM) components secondary to trauma or surgical injuries. Previous studies have shown that plasminogen activator inhibitor-1 (PAI-1) can be upregulated by hypoxia and may contribute to keloid pathogenesis. In this study we investigate the signaling mechanisms involved in hypoxia-mediated PAI-1 expression in keloid fibroblasts. Using Northern and Western blot analysis, transient transfections, and pharmacological agents, we demonstrate that hypoxia-induced upregulation of PAI-1 expression is mainly controlled by hypoxia inducible factors-1α (HIF-1α) and that hypoxia leads to a rapid and transient activation of phosphatidylinositol-3-kinase/Akt (PI3-K/Akt) and extracellular signal-regulated kinases 1/2 (ERK1/2). Treatment of cells with PI-3K/Akt inhibitor (LY294002) and tyrosine protein kinase inhibitor (genistein) significantly attenuated hypoxia-induced PAI-1 mRNA and protein expression as well as promoter activation, apparently via an inhibition of the hypoxia-induced stabilization of HIF-1α protein, attenuation of the steady-state level of HIF-1α mRNA, and its DNA-binding activity. Even though disruption of ERK1/2 signaling pathway by PD98059 abolished hypoxia-induced PAI-1 promoter activation and mRNA/protein expression in keloid fibroblasts, it did not inhibit the hypoxia-mediated stabilization of HIF-1α protein and the steady-state level of HIF-1α mRNA nor its DNA binding activity. Our findings suggest that a combination of several signaling pathways, including ERK1/2, PI3-K/Akt, and protein tyrosine kinases (PTKs), may contribute to the hypoxia-mediated induction of PAI-1 expression via activation of HIF-1α in keloid fibroblasts.",
author = "Qunzhou Zhang and Yidi Wu and Chau, {Cindy H.} and Ann, {David K.} and Charles Bertolami and Le, {Anh D.}",
year = "2004",
month = "4",
doi = "10.1002/jcp.10452",
language = "English (US)",
volume = "199",
pages = "89--97",
journal = "Journal of Cellular Physiology",
issn = "0021-9541",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - Crosstalk of Hypoxia-Mediated Signaling Pathways in Upregulating Plasminogen Activator Inhibitor-1 Expression in Keloid Fibroblasts

AU - Zhang, Qunzhou

AU - Wu, Yidi

AU - Chau, Cindy H.

AU - Ann, David K.

AU - Bertolami, Charles

AU - Le, Anh D.

PY - 2004/4

Y1 - 2004/4

N2 - Keloids are skin fibrotic conditions characterized by an excess accumulation of extracellular matrix (ECM) components secondary to trauma or surgical injuries. Previous studies have shown that plasminogen activator inhibitor-1 (PAI-1) can be upregulated by hypoxia and may contribute to keloid pathogenesis. In this study we investigate the signaling mechanisms involved in hypoxia-mediated PAI-1 expression in keloid fibroblasts. Using Northern and Western blot analysis, transient transfections, and pharmacological agents, we demonstrate that hypoxia-induced upregulation of PAI-1 expression is mainly controlled by hypoxia inducible factors-1α (HIF-1α) and that hypoxia leads to a rapid and transient activation of phosphatidylinositol-3-kinase/Akt (PI3-K/Akt) and extracellular signal-regulated kinases 1/2 (ERK1/2). Treatment of cells with PI-3K/Akt inhibitor (LY294002) and tyrosine protein kinase inhibitor (genistein) significantly attenuated hypoxia-induced PAI-1 mRNA and protein expression as well as promoter activation, apparently via an inhibition of the hypoxia-induced stabilization of HIF-1α protein, attenuation of the steady-state level of HIF-1α mRNA, and its DNA-binding activity. Even though disruption of ERK1/2 signaling pathway by PD98059 abolished hypoxia-induced PAI-1 promoter activation and mRNA/protein expression in keloid fibroblasts, it did not inhibit the hypoxia-mediated stabilization of HIF-1α protein and the steady-state level of HIF-1α mRNA nor its DNA binding activity. Our findings suggest that a combination of several signaling pathways, including ERK1/2, PI3-K/Akt, and protein tyrosine kinases (PTKs), may contribute to the hypoxia-mediated induction of PAI-1 expression via activation of HIF-1α in keloid fibroblasts.

AB - Keloids are skin fibrotic conditions characterized by an excess accumulation of extracellular matrix (ECM) components secondary to trauma or surgical injuries. Previous studies have shown that plasminogen activator inhibitor-1 (PAI-1) can be upregulated by hypoxia and may contribute to keloid pathogenesis. In this study we investigate the signaling mechanisms involved in hypoxia-mediated PAI-1 expression in keloid fibroblasts. Using Northern and Western blot analysis, transient transfections, and pharmacological agents, we demonstrate that hypoxia-induced upregulation of PAI-1 expression is mainly controlled by hypoxia inducible factors-1α (HIF-1α) and that hypoxia leads to a rapid and transient activation of phosphatidylinositol-3-kinase/Akt (PI3-K/Akt) and extracellular signal-regulated kinases 1/2 (ERK1/2). Treatment of cells with PI-3K/Akt inhibitor (LY294002) and tyrosine protein kinase inhibitor (genistein) significantly attenuated hypoxia-induced PAI-1 mRNA and protein expression as well as promoter activation, apparently via an inhibition of the hypoxia-induced stabilization of HIF-1α protein, attenuation of the steady-state level of HIF-1α mRNA, and its DNA-binding activity. Even though disruption of ERK1/2 signaling pathway by PD98059 abolished hypoxia-induced PAI-1 promoter activation and mRNA/protein expression in keloid fibroblasts, it did not inhibit the hypoxia-mediated stabilization of HIF-1α protein and the steady-state level of HIF-1α mRNA nor its DNA binding activity. Our findings suggest that a combination of several signaling pathways, including ERK1/2, PI3-K/Akt, and protein tyrosine kinases (PTKs), may contribute to the hypoxia-mediated induction of PAI-1 expression via activation of HIF-1α in keloid fibroblasts.

UR - http://www.scopus.com/inward/record.url?scp=1042291174&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1042291174&partnerID=8YFLogxK

U2 - 10.1002/jcp.10452

DO - 10.1002/jcp.10452

M3 - Article

C2 - 14978738

AN - SCOPUS:1042291174

VL - 199

SP - 89

EP - 97

JO - Journal of Cellular Physiology

JF - Journal of Cellular Physiology

SN - 0021-9541

IS - 1

ER -