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Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

Oncogene volume 19, pages 1500–1508 (2000)Cite this article

Abstract

The role of Ras and MAP kinases (MAPKs) in the regulation of erythroid differentiation was studied using a cell line (SKT6) derived from Friend virus (Anemic strain)-induced murine erythroleukemia. This cell line undergoes differentiation in vitro in response to erythropoietin (EPO) or other chemical inducers such as dimethylsulfoxide (DMSO). When a constitutively active ras mutant (ras12V) was expressed in SKT6 cells, EPO-induced differentiation was inhibited. Conversely, a dominant negative ras mutant (ras17N) induced differentiation even in the absence of EPO, suggesting that the basal Ras activity is essential for the maintenance of the undifferentiated phenotype and proliferative potential in this cell line. Rapid inactivation of ERK was observed after expression of ras17N. Slow but significant inactivation of ERK was also observed during EPO-induced differentiation. Furthermore, overexpression of a constitutively active mutant of ERK-activating kinase (MAPKK) was found to suppress erythroid differentiation, while pharmacological inhibition of MAPKK induced differentiation. These findings suggest that down-regulation of Ras/ERK signaling pathway may be an essential event in EPO-induced erythroid differentiation in this system.

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Acknowledgements

We are grateful to Dr Eisuke Nishida for the MAPKK LA-SDSE cDNA and antiserum and to Dr Hitoshi Kitayama for the mutant ras genes. We also thank Drs Naoki Oyaizu and Iyoko Kato for invaluable advice throughout this study and to Ms Mariko Nagayoshi and Mr Yoshiya Tomimori for their excellent technical assistance. This work was partly supported by a CREST grant from Japan Science and Technology Corporation.

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Authors and Affiliations

  1. Department of Retroviral Regulation, Medical Research Division, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Yushima, Tokyo, 113-8519, Japan

    Tomoko Matsuzaki, Ken-ichi Aisaki, Yasuko Yamamura & Yoji Ikawa

  2. CREST, Japan Science and Technology Corporation (JST), Kawaguchi-shi, Honcho, Saitama, 332-0012, Japan

    Tomoko Matsuzaki

  3. Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan

    Makoto Noda

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  1. Tomoko Matsuzaki
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Matsuzaki, T., Aisaki, Ki., Yamamura, Y. et al. Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line. Oncogene 19, 1500–1508 (2000). https://doi.org/10.1038/sj.onc.1203461

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