Mutant K-Ras increases GSK-3Β gene expression via an ETS-p300 transcriptional complex in pancreatic cancer

J. S. Zhang, A. Koenig, A. Harrison, A. V. Ugolkov, M. E. Fernandez-Zapico, F. J. Couch, D. D. Billadeau

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Glycogen synthase kinase-3 beta (GSK-3Β) is overexpressed in a number of human malignancies and has been shown to contribute to tumor cell proliferation and survival. Although regulation of GSK-3Β activity has been extensively studied, the mechanisms governing GSK-3Β gene expression are still unknown. Using pancreatic cancer as a model, we find that constitutively active Ras signaling increases GSK-3Β gene expression via the canonical mitogen-activated protein kinase signaling pathway. Analysis of the mechanism revealed that K-Ras regulates the expression of this kinase through two highly conserved E-twenty six (ETS) binding elements within the proximal region. Furthermore, we demonstrate that mutant K-Ras enhances ETS2 loading onto the promoter, and ETS requires its transcriptional activity to increase GSK-3Β gene transcription in pancreatic cancer cells. Lastly, we show that ETS2 cooperates with p300 histone acetyltransferase to remodel chromatin and promote GSK-3Β expression. Taken together, these results provide a general mechanism for increased expression of GSK-3Β in pancreatic cancer and perhaps other cancers, where Ras signaling is deregulated.

Original languageEnglish (US)
Pages (from-to)3705-3715
Number of pages11
JournalOncogene
Volume30
Issue number34
DOIs
StatePublished - Aug 25 2011

Keywords

  • ETS
  • GSK-3β
  • K-Ras
  • MAPK
  • pancreatic cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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