| Project/Area Number |
15390306
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | University of Yamanashi (2004-2005)
Jichi Medical University (2003) |
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Principal Investigator |
KOMATSU Norio University of Yamanashi, University of Yamanashi Hospital, Professor, 医学部附属病院, 教授 (50186798)
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| Co-Investigator(Kenkyū-buntansha) |
KIRITO Keita University of Yamanashi, University of Yamanashi Hospital, Associate Professor, 医学部附属病院, 助教授 (90306150)
永井 正 自治医科大学, 医学部, 助教授 (40237483)
森 政樹 自治医科大学, 医学部, 講師 (00337346)
内田 美栄 自治医科大学, 医学部, 助手 (80316520)
外島 正樹 自治医科大学, 医学部, 助手 (00306151)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2005: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2004: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2003: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | FKHRL1 / FOXO3a / TRAIL / APL / apoptosis / drug-sensitivity / autocrine / all-trans retinoic acid / 慢性骨髄性白血病 / imatinib / 薬剤耐性 / DNAマイクロアレイ / アポトーシス / 造血 / siRNA / トランスジェニックマウス |
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| Research Abstract |
FKHRL1 (also called FOXO3a) is a member of the FOXO subfamily of Forkhead transcription factors and lies downstream of cytokine signaling pathways. This molecule is phosphorylated by activated Akt/Gsk and remains in the cytoplasm as an "inactive form". In this study, we found that FKHRL1 functions downstream of Bcr-Abl tyrosine kinase as a phosphorylated "inactive" form in chronic myelogenous leukemia (CML). The Bcr-Abl tyrosine kinase inhibitor imatinib induced cell cycle arrest and subsequent apoptosis via the conversion of FKHRL1 from the phosphorylated "inactive" form to the dephosphorylated "active" form in CML-derived cell lines. To examine whether "active" FKHRL1 can overcome the resistance to imatinib, we generated a 4-hydroxytamoxifen (4-OHT)-inducible "active" FKHRL1 (FKHRL1-TM ; a triple mutant of FKHRL1 in which all three Akt phosphorylation sites have been mutated)-estrogen receptor fusion protein expression system in CML-derived imatinib-resistant cell lines. 4-OHT inhibited the cell growth and cell cycle progression, and subsequently induced apoptosis, accompanied by up-regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Thus, "active" FKHRL1 antagonized deregulated proliferation and induced apoptosis in these cell lines.
Moreover, we also found that all-trans retinoic acid (ATRA) induced apoptosis via FKHRL1-mediated TRAIL production in APL-derived cell line NB4 which was sensitive to ATRA. Like CML cells, over-expression of "active" FKHRL1 induced apoptosis not only in ATRA-sensitive cell line NB4 but also in ATRA-resistant NB4R cell line. Therefore, our results suggest that "active" FKHRL1 can overcome imatinib resistance and ATRA resistance in CML and APL cell lines, respectively, in part via TRAIL production.
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