Abstract
Embryonic stem (ES) cells are pluripotent cells derived from early mammalian embryos1,2. Their immortality and rapid growth make them attractive sources for stem cell therapies3; however, they produce tumours (teratomas) when transplanted, which could preclude their therapeutic usage4. Why ES cells, which lack chromosomal abnormalities, possess tumour-like properties is largely unknown. Here we show that mouse ES cells specifically express a Ras-like gene, which we have named ERas. We show that human HRasp, which is a recognized pseudogene, does not contain reported base substitutions and instead encodes the human orthologue of ERas. This protein contains amino-acid residues identical to those present in active mutants of Ras5 and causes oncogenic transformation in NIH 3T3 cells. ERas interacts with phosphatidylinositol-3-OH kinase6 but not with Raf7,8. ERas-null ES cells maintain pluripotency but show significantly reduced growth and tumorigenicity, which are rescued by expression of ERas complementary DNA or by activated phosphatidylinositol-3-OH kinase. We conclude that the transforming oncogene ERas is important in the tumour-like growth properties of ES cells.
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Acknowledgements
We thank E. Kaiho, Y. Tokuzawa and M. Murakami for discussion; C. Takigawa and J. Iida for technical assistance; T. Ichisaka and Y. Samitsu for blastocyst microinjection; R. Farese Jr for RF8 ES cells, R. Jaenisch and T. Noda for J1 cells; W. Skarnes and S. Young for CGR8 cells; H. Niwa for MG1.19 cells, pCAG-IP and pBIKS(- )BgeopA; M. Okabe and J.-i. Miyazaki for pCX–EGFP; K. Kohno and T. Kitamura for PLAT-E cells and pMX retroviral vectors; and S. Young, R. Farese Jr and R. Pitas for critically reading the manuscript.
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Takahashi, K., Mitsui, K. & Yamanaka, S. Role of ERas in promoting tumour-like properties in mouse embryonic stem cells. Nature 423, 541–545 (2003). https://doi.org/10.1038/nature01646
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DOI: https://doi.org/10.1038/nature01646