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Mol Cell Biol, July 1998, p. 4282-4290, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Involvement of Prolonged Ras Activation in Thrombopoietin-Induced Megakaryocytic Differentiation of a Human Factor-Dependent Hematopoietic Cell Line

Itaru Matsumura,1 Koichi Nakajima,2 Hiroshi Wakao,3 Seisuke Hattori,4 Koji Hashimoto,5 Hiroyuki Sugahara,1 Takashi Kato,6 Hiroshi Miyazaki,6 Toshio Hirano,2 and Yuzuru Kanakura1 *

Department of Hematology and Oncology,1 Molecular Oncology, Biomedical Research Center,2 and Internal Medicine II,5 Osaka University Medical School, Suita, Osaka 565-0871, Helix Research Institute, Chiba 292-0812,3 National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-0032,4 and Pharmaceutical Research Laboratory, Kirin Brewery Co. Ltd., Takasaki, Gunma 370-1202,6 Japan

Received 17 February 1998/Returned for modification 31 March 1998/Accepted 25 April 1998

Thrombopoietin (TPO) is a hematopoietic growth factor that plays fundamental roles is both megakaryopoiesis and thrombopoiesis through binding to its receptor, c-mpl. Although TPO has been shown to activate various types of intracellular signaling molecules, such as the Janus family of protein tyrosine kinases, signal transducers and activators of transcription (STATs), and ras, the precise mechanisms underlying TPO-induced proliferation and differentiation remain unknown. In an effort to clarify the mechanisms of TPO-induced proliferation and differentiation, c-mpl was introduced into F-36P, a human interleukin-3 (IL-3)-dependent erythroleukemia cell line, and the effects of TPO on the c-mpl-transfected F-36P (F-36P-mpl) cells were investigated. F-36P-mpl cells were found to proliferate and differentiate at a high rate into mature megakaryocytes in response to TPO. Dominant-negative (dn) forms of STAT1, STAT3, STAT5, and ras were inducibly expressed in F-36P-mpl cells, and their effects on TPO-induced proliferation and megakaryocytic differentiation were analyzed. Among these dn molecules, both dn ras and dn STAT5 reduced TPO- or IL-3-induced proliferation of F-36P-mpl cells by ~30%, and only dn ras could inhibit TPO-induced megakaryocytic differentiation. In accord with this result, overexpression of activated ras (H-rasG12V) for 5 days led to megakaryocytic differentiation of F-36P-mpl cells. In a time course analysis on H-rasG12V-induced differentiation, activation of the ras pathway for 24 to 28 h was required and sufficient to induce megakaryocytic differentiation. Consistent with this result, the treatment of F-36P-mpl cells with TPO was able to induce prolonged activation of ras for more than 24 h, whereas IL-3 had only a transient effect. These results suggest that prolonged ras activation may be involved in TPO-induced megakaryocytic differentiation.

* Corresponding author. Mailing address: Department of Hematology and Oncology, Osaka University Medical School, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-879-3871. Fax: 81-6-879-3879. E-mail: kanakura{at}bldon.med.osaka-u.ac.jp.

Mol Cell Biol, July 1998, p. 4282-4290, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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