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Human diploid fibroblasts are resistant to MEK/ERK-mediated disruption of the actin cytoskeleton and invasiveness stimulated by Ras

Oncogene volume 24, pages 5648–5655 (2005)Cite this article

A Corrigendum to this article was published on 08 December 2005

Abstract

Ras-induced transformation is characterized not only by uncontrolled proliferation but also by drastic morphological changes accompanied by the disruption of the actin cytoskeleton. Previously, we reported that human fibroblasts are more resistant than rodent fibroblasts to Ras-induced transformation. To explore the molecular basis for the difference in susceptibility to Ras-induced transformation, we investigated the effect of activated H-Ras on the actin cytoskeleton in human diploid fibroblasts and in rat embryo fibroblasts, both of which are immortalized by SV40 early region. We demonstrate here that Ras-induced morphological changes, decreased expression of tropomyosin isoforms, and suppression of the ROCK/LIMK/Cofilin pathway observed in the rat fibroblasts were not detected in the human fibroblasts even with high expression levels of Ras. We also show that activation of the MEK/ERK pathway sufficed to induce all of these alterations in the rat fibroblasts, whereas the human fibroblasts were refractory to these MEK/ERK-mediated changes. In addition to morphological changes, we demonstrated that the expression of activated Ras induced an invasive phenotype in the rat, but not in the human fibroblasts. These studies provide evidence for the existence of human-specific mechanisms that resist Ras/MEK/ERK-mediated transformation.

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Acknowledgements

We are grateful to E Nishda, H Inoue, T Shishido, P Sharp, and R Weinberg for providing the reagents. We thank T Hirano, HJ Okano and M Yutsudo for generous support to this study. We also thank David Foster for critical reading of our manuscript. This work was supported by a grant from the program Grants-in-Aid for Specially Promoted Research of the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by funding from Osaka City.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, 565-0874, Osaka, Japan

    Taiko Sukezane, Chitose Oneyama, Kyoko Kakumoto, Kana Shibutani, Hidesaburo Hanafusa & Tsuyoshi Akagi

  2. Department of Molecular Oncology (C7), Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Taiko Sukezane

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  1. Taiko Sukezane
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Correspondence to Tsuyoshi Akagi.

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Sukezane, T., Oneyama, C., Kakumoto, K. et al. Human diploid fibroblasts are resistant to MEK/ERK-mediated disruption of the actin cytoskeleton and invasiveness stimulated by Ras. Oncogene 24, 5648–5655 (2005). https://doi.org/10.1038/sj.onc.1208724

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