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Apoptosis and differentiation of human embryonic stem cells induced by sustained activation of c-Myc

Oncogene volume 26, pages 5564–5576 (2007)Cite this article

Abstract

Embryonic stem (ES) cells are self-renewing, pluripotent cell lines, characterized by their potential to differentiate into all cell types. The proto-oncogene product c-Myc has a crucial role in the self-renewal of mouse ES (mES) cells, but its role in human ES (hES) cells is unknown. To investigate c-Myc functions in hES cells, we expressed an inducible c-Myc fused to the hormone-binding domain of the estrogen receptor (c-MycER) protein that is activated by 4-hydroxy-tamoxifen. In contrast to its role in mES cells, activation of c-MycER in hES cells induced apoptosis and differentiation into extraembryonic endoderm and trophectoderm lineages concomitant with reduced expression of the pluripotent markers Oct4 and Nanog. Neither inhibition of caspase activity nor knockdown of p53 by RNA interference impaired the induction of differentiation markers induced by c-Myc activation. In addition, differentiation induced by c-Myc activation was associated with downregulation of α6 integrin expression, suggesting an important role for the integrin/extracellular matrix interaction in the regulation of ES cell behavior. None of these effects occurred with deletion of the c-Myc transactivation domain, indicating that c-Myc promotes both apoptosis and differentiation in a transcriptional activity-dependent manner. Together, our results provide new insights into the c-Myc functions regulating hES cell fate.

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Acknowledgements

We thank Dr Pierre Chambon (IGBMC, France) for the kind gift of the pCreERT2 plasmid, and members of the Nakatsuji's laboratory for valuable comments and discussions on the manuscript. This work was supported in part by the National BioResource Project of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), and by the Japan Society for the Promotion of Science.

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  1. Laboratory of Embryonic Stem Cell Research, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

    T Sumi, N Tsuneyoshi, N Nakatsuji & H Suemori

  2. Department of Development and Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

    N Tsuneyoshi & N Nakatsuji

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  1. T Sumi
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Correspondence to H Suemori.

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Sumi, T., Tsuneyoshi, N., Nakatsuji, N. et al. Apoptosis and differentiation of human embryonic stem cells induced by sustained activation of c-Myc. Oncogene 26, 5564–5576 (2007). https://doi.org/10.1038/sj.onc.1210353

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