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

Shuying Liu, Xianjun Fang, Hassan Hall, Shuangxing Yu, Debra Smith, Zhimin Lu, Dexing Fang, Jinsong Liu, L. Clifton Stephens, James R. Woodgett, Gordon Mills

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)5248-5253
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number13
DOIs
StatePublished - Apr 1 2008
Externally publishedYes

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Glycogen Synthase Kinase 3
Catenins
Fibroblasts
Embryonic Structures
Cyclin D1
Neoplastic Cell Transformation
Oncogenes
Small Interfering RNA
Up-Regulation
Phenotype
Growth

Keywords

  • β-catenin
  • Cyclin D1
  • GSK3β

ASJC Scopus subject areas

  • General

Cite this

Homozygous deletion of glycogen synthase kinase 3β bypasses senescence allowing Ras transformation of primary murine fibroblasts. / Liu, Shuying; Fang, Xianjun; Hall, Hassan; Yu, Shuangxing; Smith, Debra; Lu, Zhimin; Fang, Dexing; Liu, Jinsong; Stephens, L. Clifton; Woodgett, James R.; Mills, Gordon.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 13, 01.04.2008, p. 5248-5253.

Research output: Contribution to journalArticle

Liu, Shuying ; Fang, Xianjun ; Hall, Hassan ; Yu, Shuangxing ; Smith, Debra ; Lu, Zhimin ; Fang, Dexing ; Liu, Jinsong ; Stephens, L. Clifton ; Woodgett, James R. ; Mills, Gordon. / Homozygous deletion of glycogen synthase kinase 3β bypasses senescence allowing Ras transformation of primary murine fibroblasts. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 13. pp. 5248-5253.
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AU - Hall, Hassan

AU - Yu, Shuangxing

AU - Smith, Debra

AU - Lu, Zhimin

AU - Fang, Dexing

AU - Liu, Jinsong

AU - Stephens, L. Clifton

AU - Woodgett, James R.

AU - Mills, Gordon

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AB - 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.

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