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J. Biol. Chem., Vol. 276, Issue 18, 15082-15089, May 4, 2001

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Forkhead Family Transcription Factor FKHRL1 Is Expressed in Human Megakaryocytes
REGULATION OF CELL CYCLING AS A DOWNSTREAM MOLECULE OF THROMBOPOIETIN SIGNALING^*

Masaru Tanaka, Keita Kirito, Yoshifumi Kashii^§, Mie Uchida, Tomoko Watanabe, Hitoshi Endo^¶, Tomoyuki Endoh, Ken-ichi Sawada, Keiya Ozawa, and Norio Komatsu^**

From the Departments of  Hematology, ^§ Pediatrics, and ^¶ Biochemistry, Jichi Medical School, Tochigi, 329-0498 Japan and the  Department of Internal Medicine II, Hokkaido University School of Medicine, Sapporo, Japan

FKHRL1, a member of the Forkhead transcription factor family, is one of the downstream molecules of phosphatidylinositol 3-kinase-Akt. This molecule is a mammalian homolog of DAF-16, which plays an important role in the longevity of Caenorhabditis elegans. In this study we found that Akt and FKHRL1 proteins were detectable in highly purified normal human megakaryocytes and that these molecules were actually phosphorylated by thrombopoietin (TPO). To clarify the functional role of FKHRL1 in TPO signaling, we established a tetracycline-inducible system in the human TPO-dependent leukemia cell line UT-7/TPO. Induced expression of active FKHRL1 led to cell cycle arrest at G₀/G₁ phase in this cell line. These results suggest that FKHRL1 plays an important role in the cell cycle of megakaryocytic cells as one of the downstream target molecules of phosphatidylinositol 3-kinase-Akt, presumably mediated through the activation or inactivation of cell cycle-associated gene(s).

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