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Originally published In Press as doi:10.1074/jbc.M211562200 on November 26, 2002

J. Biol. Chem., Vol. 278, Issue 8, 6411-6419, February 21, 2003
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A Member of Forkhead Transcription Factor FKHRL1 Is a Downstream Effector of STI571-induced Cell Cycle Arrest in BCR-ABL-expressing Cells*

Norio KomatsuDagger §, Tomoko WatanabeDagger , Mie UchidaDagger , Masaki MoriDagger , Keita KiritoDagger , Satoru KikuchiDagger , Qifa LiuDagger , Tetsuzo Tauchi||, Keisuke Miyazawa||, Hitoshi Endo**, Tadashi NagaiDagger , and Keiya OzawaDagger

From the Dagger  Division of Hematology, Department of Medicine, Jichi Medical School, Tochigi 329-0498, the || First Department of Internal Medicine, Tokyo Medical University, Tokyo 160-8402, and the ** Department of Biochemistry, Jichi Medical School, Tochigi 329-0498, Japan

A member of the Forkhead transcription factor family, FKHRL1, lies downstream of the phosphatidylinositol 3-kinase-Akt activation pathway in cytokine signaling. Because the phosphatidylinositol 3-kinase-Akt activation pathway is required for BCR-ABL-mediated transformation and survival signaling in chronic myelogenous leukemia (CML), in this study we examined the involvement of FKHRL1 in the BCR-ABL-mediated signaling pathway. FKHRL1 was constitutively phosphorylated in BCR-ABL-expressing cell lines KCL22 and KU812, and its phosphorylation was inhibited by treatment with STI571, a specific inhibitor of BCR-ABL tyrosine kinase. Concomitantly, STI571 induced cell cycle arrest at the G0/G1 phase, accompanied by up-regulation of a cyclin-dependent kinase inhibitor p27/Kip1 in KCL22 cells. In addition, FKHRL1 was constitutively phosphorylated in the TF-1/bcr-abl cell line ectopically expressing BCR-ABL but not in the parent TF-1 cell line. Considering several lines of evidence that phosphorylated FKHRL1 has lost transcriptional activity and that p27/Kip1 expression is positively regulated by dephosphorylated "active" FKHRL1, BCR-ABL may down-regulate p27/Kip1 expression via the loss of FKHRL1 function as a transcription factor. To demonstrate this hypothesis, we generated a tamoxifen-inducible "active FKHRL1" FKHRL1-TM (a triple mutant of FKHRL1, in which all three Akt phosphorylation sites have been mutated), estrogen receptor system in the KCL22 cell line. The addition of tamoxifen inhibited the cell growth indicating that overexpression of FKHRL1 in the nucleus antagonized deregulated proliferation of CML cells. Collectively, FKHRL1 regulates the expression of p27/Kip1 as a downstream molecule of BCR-ABL signaling in CML cells. BCR-ABL-induced loss of FKHRL1 function may be involved in oncogenic transformation of CML partially via the down-regulation of p27/Kip1 proteins.

* This work was supported by grants-in-aid for Cancer Research and Scientific Research from the Ministry of Education, Science, and Culture of Japan, by grants from the Yamanouchi Foundation for Research on Metabolic Disorders, and the Mochida Memorial 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.

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

Present address: Dept. of Hematology, Nanfang Hospital, Guangzhou city, Guangdong 510515, China.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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