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Homozygous deletion of glycogen synthase kinase 3beta bypasses senescence allowing Ras transformation of primary murine fibroblasts.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2008 Apr 01; Vol. 105 (13), pp. 5248-53. Date of Electronic Publication: 2008 Mar 26. - Publication Year :
- 2008
-
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.
- Subjects :
- Active Transport, Cell Nucleus
Animals
Catalysis
Cells, Cultured
Cyclin D1 metabolism
Fibroblasts
Gene Expression Regulation
Glycogen Synthase Kinase 3 genetics
Glycogen Synthase Kinase 3 beta
Mice
Mice, Knockout
beta Catenin metabolism
ras Proteins genetics
Cellular Senescence physiology
Gene Deletion
Glycogen Synthase Kinase 3 deficiency
Glycogen Synthase Kinase 3 metabolism
Homozygote
Transgenes genetics
ras Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 105
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 18367674
- Full Text :
- https://doi.org/10.1073/pnas.0704242105