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Originally published In Press as doi:10.1074/jbc.M109824200 on December 27, 2001

J. Biol. Chem., Vol. 277, Issue 10, 8329-8337, March 8, 2002
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Thrombopoietin Regulates Bcl-xL Gene Expression through Stat5 and Phosphatidylinositol 3-Kinase Activation Pathways*

Keita Kirito§, Tomoko Watanabe§, Ken-ichi Sawada||, Hitoshi Endo, Keiya Ozawa§, and Norio Komatsu§Dagger

From the § Division of Hematology, Department of Medicine, and the  Department of Biochemistry, Jichi Medical School, Tochigi 329-04 and the || Department of Internal Medicine II, Hokkaido University School of Medicine, Sapporo 060-8638, Japan

Thrombopoietin (TPO), an essential factor for megakaryopoiesis and thrombopoiesis, works as a survival factor for megakaryocytic lineage cells. However, little is known about the molecular mechanism in detail. We show here that TPO supports the survival of TPO-dependent leukemia cell line UT-7/TPO and normal megakaryocytic progenitors via the induction of Bcl-xL, an anti-apoptotic member of the Bcl-2 family. We further analyzed the signal transduction pathways required for TPO-induced Bcl-xL gene expression. A reporter assay with various lengths of Bcl-x gene promoter revealed that both Stat- and nuclear factor kappa B-binding sites are prerequisites for TPO-induced promoter activity. Consistent with these results, TPO induced the binding of Stat5 and subunits of nuclear factor kappa B, p50, and c-Rel to the Bcl-x gene promoter. AG490, a specific inhibitor for Jak2, and LY294002, a specific inhibitor for phosphatidylinositol (PI) 3-kinase, reduced the protein level of Bcl-xL in UT-7/TPO cells, accompanied by an increase in the ratio of apoptotic cells. Interestingly, LY294002 enhanced the TPO-induced DNA binding activity of Stat5 without affecting the Jak2 activation and tyrosine phosphorylation of Stat5. Concomitantly, confocal microscopy revealed that LY294002 clearly inhibited the nuclear export of Stat5, suggesting that PI 3-kinase regulates the subcellular localization of Stat5. Taken together, our results suggest that both Jak-Stat and PI 3-kinase activation pathways regulate the TPO-induced survival of megakaryocytic cells via Bcl-xL gene expression. In addition, our data suggest possible cross-talk between these two signaling pathways.

* This work was supported by grants-in-aid for cancer research and scientific research from the Ministry of Education, Science, Sports and Culture of Japan and by grants from the Yamanouchi Foundation for Research on Metabolic Disorders and Mochida Medical and Pharmaceutical Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Division of Hematology, Dept. of Medicine, Jichi Medical School, Minamikawachi-machi, Tochigi-ken 329-0498, Japan. Tel.: 81-285-58-7353; Fax: 81-285-44-5258; E-mail: nkomatsu@jichi.ac.jp.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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