Both mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) 1/2 and phosphatidylinositide-3-OH kinase (PI3K)/Akt pathways regulate activation of E-twenty-six (ETS)-like transcription factor 1 (Elk-1) in U138 glioblastoma cells

Int J Biochem Cell Biol. 2012 Feb;44(2):302-10. doi: 10.1016/j.biocel.2011.10.025. Epub 2011 Nov 7.

Abstract

Epidermal growth factor (EGF) and its receptor (EGFR) have been shown to play a significant role in the pathogenesis of glioblastoma. In our study, the EGFR was stimulated with EGF in human U138 glioblastoma cells. We show that the activated mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) 1/2 pathway phosphorylated the E twenty-six (ETS)-like transcription factor 1 (Elk-1) mainly at serine 383 residue. Mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, UO126 and ERK inhibitor II, FR180204 blocked the Elk-1 phosphorylation and activation. The phosphatidylinositide-3-OH kinase (PI3K)/Akt pathway was also involved in the Elk-1 activation. Activation of the Elk-1 led to an increased survival and a proliferative response with the EGF stimulation in the U138 glioblastoma cells. Knocking-down the Elk-1 using an RNA interference technique caused a decrease in survival of the unstimulated U138 glioblastoma cells and also decreased the proliferative response to the EGF stimulation. The Elk-1 transcription factor was important for the survival and proliferation of U138 glioblastoma cells upon the stimulation of EGFR with EGF. The MAPK/ERK1/2 and PI3K/Akt pathways regulated this response via activation of the Elk-1 transcription factor. The Elk-1 may be one of the convergence points for pathways located downstream of EGFR in glioblastoma cells. Utilization of the Elk-1 as a therapeutic target may lead to a novel strategy in treatment of glioblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Epidermal Growth Factor / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Glioblastoma / enzymology
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • ets-Domain Protein Elk-1 / metabolism*

Substances

  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Epidermal Growth Factor
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3