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Papers In Press, published online ahead of print December 27, 2001
J. Biol. Chem, 10.1074/jbc.M109824200
Submitted on October 11, 2001
Revised on November 26, 2001
Accepted on December 27, 2001

TPO 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

Division of Hematology, Jichi Medical School, Kawachi-gun, Tochigi-ken 329-0498

Corresponding Author: nkomatsu{at}jichi.ac.jp

Thrombopoietin (TPO), an essential factor for megakaryopoiesis and thromobopoiesis, 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 NF-kB-binding sites are prerequisites for TPO-induced promoter activity. Consistent with these results, TPO induced the binding of Stat5 and subunits of NF-kB, p50 and c-Rel to the Bcl-x gene promoter. AG490, a specific inhibitor for Jak2, and LY294002, a specific inhibitor for phosphatidylinositol-3 (PI3) 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 PI3 kinase regulates the subcellular localization of Stat5. Taken together, our results suggest that both Jak-Stat and PI3 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.


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