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


ABSTRACT: Glycogen synthase kinase-3 beta (GSK-3?) is overexpressed in a number of human malignancies and has been shown to contribute to tumor cell proliferation and survival. Although regulation of GSK-3? activity has been extensively studied, the mechanisms governing GSK-3? gene expression are still unknown. Using pancreatic cancer as a model, we find that constitutively active Ras signaling increases GSK-3? 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-3? gene transcription in pancreatic cancer cells. Lastly, we show that ETS2 cooperates with p300 histone acetyltransferase to remodel chromatin and promote GSK-3? expression. Taken together, these results provide a general mechanism for increased expression of GSK-3? in pancreatic cancer and perhaps other cancers, where Ras signaling is deregulated.

SUBMITTER: Zhang JS 

PROVIDER: S-EPMC3162070 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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

Zhang J-S JS   Koenig A A   Harrison A A   Ugolkov A V AV   Fernandez-Zapico M E ME   Couch F J FJ   Billadeau D D DD  

Oncogene 20110328 34


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  ...[more]

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