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

Oncogene volume 30, pages 3705–3715 (2011)Cite this article

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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.

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Acknowledgements

Mayo Clinic Pancreatic Cancer SPORE grant CA102701 (DDB and MEF-Z). DDB is a Leukemia and Lymphoma Scholar. AK is supported by a Mildred-Scheel fellowship of German Cancer Society.

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Author notes

  1. A V Ugolkov

    Present address: Current address: Department of Pathology, Northwestern University, Chicago, IL, USA.,

  2. J-S Zhang and A Koenig: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology and Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, USA

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

  2. Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany

    A Koenig

  3. Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

    F J Couch

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  1. J-S Zhang
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Correspondence to J-S Zhang or D D Billadeau.

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Zhang, JS., Koenig, A., Harrison, A. et al. Mutant K-Ras increases GSK-3β gene expression via an ETS-p300 transcriptional complex in pancreatic cancer. Oncogene 30, 3705–3715 (2011). https://doi.org/10.1038/onc.2011.90

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