Trophoblast apoptosis is inhibited by hepatocyte growth factor through the Akt and beta-catenin mediated up-regulation of inducible nitric oxide synthase

Cell Signal. 2005 May;17(5):571-80. doi: 10.1016/j.cellsig.2004.09.015.

Abstract

Excessive apoptosis of trophoblast cells is thought to be a contributing factor in complications of pregnancy such as pre-eclampsia. Hepatocyte growth factor (HGF) inhibits apoptosis in trophoblasts and we have investigated the signalling pathways through which this anti-apoptotic effect is mediated. Treatment of cells with HGF led to rapid phosphorylation of Akt while an Akt inhibitor blocked the protective effect of HGF. Glycogen synthase kinase-3beta (GSK-3beta) was found to be one of the downstream targets of Akt. HGF treatment inactivated GSK-3beta which in turn led to the activation of the transcription factor beta-catenin. Pharmacological inhibition of GSK-3beta, independently of HGF treatment, strongly increased both beta-catenin activity and cell survival, suggesting that beta-catenin alone has a pronounced anti-apoptotic effect. We also found that both HGF treatment and pharmacological activation of beta-catenin leads to increased expression of inducible nitric oxide synthase (iNOS). We suggest that the Akt mediated activation of beta-catenin leads to inhibition of trophoblast apoptosis following increased expression of iNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / drug effects
  • Caspases / metabolism
  • Cytoskeletal Proteins / metabolism*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hepatocyte Growth Factor / pharmacology*
  • Humans
  • I-kappa B Proteins / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase / biosynthesis*
  • Nitric Oxide Synthase / physiology
  • Nitric Oxide Synthase Type II
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • Trans-Activators / metabolism*
  • Trophoblasts / cytology
  • Trophoblasts / enzymology
  • Trophoblasts / metabolism*
  • Up-Regulation
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Proto-Oncogene Proteins
  • Trans-Activators
  • beta Catenin
  • NF-KappaB Inhibitor alpha
  • Hepatocyte Growth Factor
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • AKT1 protein, human
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Caspases