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Role of ERas in promoting tumour-like properties in mouse embryonic stem cells

Nature volume 423, pages 541–545 (2003)Cite this article

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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Figure 1: Identification of ERas.
Figure 2: Transformation by ERas.
Figure 3: Role of ERas in ES cell growth.
Figure 4: PI(3)K activation by ERas.

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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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  1. Laboratory of Animal Molecular Technology, Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Ikoma, 630-0192, Nara, Japan

    Kazutoshi Takahashi, Kaoru Mitsui & Shinya Yamanaka

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  1. Kazutoshi Takahashi
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Correspondence to Shinya Yamanaka.

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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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