title: Homozygous deletion of glycogen synthase kinase 3beta bypasses senescence allowing Ras transformation of primary murine fibroblasts.
abstract: In primary mammalian cells, expression of oncogenes such as activated Ras induces premature senescence rather than transformation. We show that homozygous deletion of glycogen synthase kinase (GSK) 3beta (GSK3beta-/-) bypasses senescence induced by mutant Ras(V12) allowing primary mouse embryo fibroblasts (MEFs) as well as immortalized MEFs to exhibit a transformed phenotype in vitro and in vivo. Both catalytic activity and Axin-binding of GSK3beta are required to optimally suppress Ras transformation. The expression of Ras(V12) in GSK3beta-/-, but not in GSK3beta+/+ MEFs results in translocation of beta-catenin to the nucleus with concomitant up-regulation of cyclin D1. siRNA-mediated knockdown of beta-catenin decreases both cyclin D1 expression and anchorage-independent growth of transformed cells indicating a causal role for beta-catenin. Thus Ras(V12) and the lack of GSK3beta act in concert to activate the beta-catenin pathway, which may underlie the bypass of senescence and tumorigenic transformation by Ras.
authors: Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors: Shuying
authors: S
authors: Liu
authors: Xianjun
authors: X
authors: Fang
authors: Hassan
authors: H
authors: Hall
authors: Shuangxing
authors: S
authors: Yu
authors: Debra
authors: D
authors: Smith
authors: Zhimin
authors: Z
authors: Lu
authors: Dexing
authors: D
authors: Fang
authors: Jinsong
authors: J
authors: Liu
authors: L Clifton
authors: LC
authors: Stephens
authors: James R
authors: JR
authors: Woodgett
authors: Gordon B
authors: GB
authors: Mills
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D019938:Cyclin D1 / Q000378:metabolism; D005347:Fibroblasts; D017353:Gene Deletion; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D019076:Transgenes / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D019938:Cyclin D1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018631:ras Proteins