title: Mutant K-Ras increases GSK-3β gene expression via an ETS-p300 transcriptional complex in pancreatic cancer.
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.
authors: Department of Immunology and Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, USA. zhang.jinsan@mayo.edu
authors: J-S
authors: JS
authors: Zhang
authors: A
authors: A
authors: Koenig
authors: A
authors: A
authors: Harrison
authors: A V
authors: AV
authors: Ugolkov
authors: M E
authors: ME
authors: Fernandez-Zapico
authors: F J
authors: FJ
authors: Couch
authors: D D
authors: DD
authors: Billadeau
mesh_terms: D000818:Animals; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D011905:Genes, ras; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D034802:RNA-Binding Protein EWS / Q000235:genetics*; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000235:genetics*
chemical_list: D034802:RNA-Binding Protein EWS; D050880:p300-CBP Transcription Factors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3