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) 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) |
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Pages (from-to) | 5248-5253 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 105 |
Issue number | 13 |
DOIs | |
State | Published - Apr 1 2008 |
Externally published | Yes |
Keywords
- Cyclin D1
- GSK3β
- β-catenin
ASJC Scopus subject areas
- General