Homozygous deletion of glycogen synthase kinase 3beta bypasses senescence allowing Ras transformation of primary murine fibroblasts.

@article{citeulike:3243222, 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.}, address = {Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.}, author = {Liu, S. and Fang, X. and Hall, H. and Yu, S. and Smith, D. and Lu, Z. and Fang, D. and Liu, J. and Stephens, L. C. and Woodgett, J. R. and Mills, G. B. }, citeulike-article-id = {3243222}, doi = {http://dx.doi.org/10.1073/pnas.0704242105}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {fibroblast, gsk, ras, senescence}, month = {April}, number = {13}, pages = {5248--5253}, posted-at = {2008-09-15 04:50:38}, priority = {2}, title = {Homozygous deletion of glycogen synthase kinase 3beta bypasses senescence allowing Ras transformation of primary murine fibroblasts.}, url = {http://dx.doi.org/10.1073/pnas.0704242105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:3243222 L3 - citeulike-article-id:3243222 N2 - 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. IS - 13 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 1091-6490 AD - Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. EP - 5253 TI - Homozygous deletion of glycogen synthase kinase 3beta bypasses senescence allowing Ras transformation of primary murine fibroblasts. VL - 105 SP - 5248 KW - fibroblast KW - gsk KW - ras KW - senescence AU - Liu, S AU - Fang, X AU - Hall, H AU - Yu, S AU - Smith, D AU - Lu, Z AU - Fang, D AU - Liu, J AU - Stephens, LC AU - Woodgett, JR AU - Mills, GB PY - 2008/04/01/ UR - http://dx.doi.org/10.1073/pnas.0704242105 ER -