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Regulation of the hypoxia-dependent plasminogen activator inhibitor 1 expression by MAP kinases

Thomas Kietzmann1, Kurt Jungermann, Agnes Görlach

  • 1Institut für Biochemie und Molekulare Zellbiologie, Humboldtallee 23, D-37073 Göttingen, Germany. tkietzmn@gwdg.de

Thrombosis and Haemostasis
|April 2, 2003
PubMed

Insights

Mitogen-activated protein kinases (MAPKs) and protein kinase B (PKB) influence hypoxia-induced plasminogen activator inhibitor-1 (PAI-1) expression. These signaling pathways, particularly p38 and PKB, enhance PAI-1 levels during the hypoxic response.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Hypoxia research

Background:

  • Mitogen-activated protein kinases (MAPKs) and protein kinase B (PKB) are key mediators of cellular growth and stress responses.
  • These signaling pathways have been implicated in the cellular response to hypoxia (low oxygen conditions).
  • Hypoxia-inducible factor 1 (HIF-1) is the primary regulator of plasminogen activator inhibitor-1 (PAI-1) expression under hypoxia, but the roles of MAPKs and PKB in this process are not fully understood.

Purpose of the Study:

  • To investigate the involvement of MAPKs and PKB in the regulation of PAI-1 expression during hypoxia.
  • To elucidate the specific roles of p38 and PKB signaling in HIF-1-mediated PAI-1 induction.

Main Methods:

  • Utilized HepG2 cells treated with specific inhibitors (SB203580 for p38, LY294002 for PI3K, PD98059 for MEK1).
  • Employed overexpression of PKB, p38 upstream kinases (MKK6, MKK3), JNK, and ERK.
  • Assessed PAI-1 mRNA levels and reporter gene activity (luciferase assays) using hypoxia-inducible and HIF-dependent constructs.
  • Measured HIF-1alpha protein levels.

Main Results:

  • Inhibition of p38 (SB203580) and PI3K (LY294002) abrogated hypoxia-induced PAI-1 expression, while MEK1 inhibition (PD98059) had no effect.
  • Overexpression of PKB, MKK6, MKK3, and JNK, but not ERK, led to increased PAI-1 mRNA levels.
  • Cells overexpressing MKK3, MKK6, or PKB showed enhanced PAI-1 promoter activity and increased HIF-1alpha protein levels.

Conclusions:

  • The p38 and PKB signaling pathways play a significant role in enhancing PAI-1 levels during the hypoxic response.
  • These pathways contribute to the regulation of HIF-1alpha protein levels and subsequent PAI-1 induction under low oxygen conditions.

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