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 language | English (US) |
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Pages (from-to) | 3705-3715 |
Number of pages | 11 |
Journal | Oncogene |
Volume | 30 |
Issue number | 34 |
DOIs | |
State | Published - Aug 25 2011 |
Funding
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.
Keywords
- ETS
- GSK-3β
- K-Ras
- MAPK
- pancreatic cancer
ASJC Scopus subject areas
- Genetics
- Molecular Biology
- Cancer Research