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) 3β (GSK3β-/-) bypasses senescence induced by mutant RasV12 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 GSK3β are required to optimally suppress Ras transformation. The expression of RasV12 in GSK3β-/-, but not in GSK3β+/+ MEFs results in translocation of β-catenin to the nucleus with concomitant up-regulation of cyclin D1. siRNA-mediated knockdown of β-catenin decreases both cyclin D1 expression and anchorage-independent growth of transformed cells indicating a causal role for β-catenin. Thus RasV12 and the lack of GSK3β act in concert to activate the β-catenin pathway, which may underlie the bypass of senescence and tumorigenic transformation by Ras.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Apr 1 2008|
- Cyclin D1
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