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

J-S Zhang1, A Koenig, A Harrison

  • 1Department of Immunology and Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, USA. zhang.jinsan@mayo.edu

Oncogene
|March 29, 2011
PubMed

Insights

Ras signaling activates Glycogen synthase kinase-3 beta (GSK-3β) gene expression in pancreatic cancer. This occurs through the ETS2 transcription factor and p300 histone acetyltransferase, promoting tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Glycogen synthase kinase-3 beta (GSK-3β) is implicated in human malignancies, yet its gene expression regulation remains unclear.
  • Understanding GSK-3β gene expression mechanisms is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms controlling GSK-3β gene expression in pancreatic cancer.
  • To investigate the role of Ras signaling in regulating GSK-3β expression.

Main Methods:

  • Utilized pancreatic cancer models to study gene expression.
  • Analyzed the involvement of mitogen-activated protein kinase (MAPK) and ETS transcription factors.
  • Investigated the interaction between ETS2 and p300 histone acetyltransferase.

Main Results:

  • Constitutively active Ras signaling upregulates GSK-3β gene expression via the MAPK pathway.
  • K-Ras specifically targets ETS binding elements on the GSK-3β promoter.
  • Mutant K-Ras enhances ETS2 binding and transcriptional activity, increasing GSK-3β expression.
  • ETS2 collaborates with p300 to remodel chromatin and drive GSK-3β transcription.

Conclusions:

  • Established a novel mechanism for increased GSK-3β expression in pancreatic cancer driven by Ras signaling.
  • Identified ETS2 and p300 as key regulators of GSK-3β gene transcription.
  • This pathway may be relevant for other cancers with deregulated Ras signaling.

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