| Project/Area Number |
15570154
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
SHIRAKATA Masaki Tokyo Medical and Dental University, Medical Research Institute, Research assistant, 難治疾患研究所, 助手 (70251551)
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| Co-Investigator(Kenkyū-buntansha) |
YAMANASHI Yuji Tokyo Medical and Dental University, Medical Research Institute, Professor, 難治疾患研究所, 教授 (40202387)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | Cell cycle reguration / Cell growth / Cancer / Apoptosis / シグナル伝達 / 細胞周期 / ゲノム複製 / EBウイルス / MAPK |
|---|
| Research Abstract |
Dok-1 and Dok-2 are rasGAP-associated adaptor proteins expressed preferentially in hematopoietic cells. We found that Dok-1 plays an important role of cell cycle progression in cultured cells. We also generated mice lacking Dok-1 and/or Dok-2 ; among them, the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia. The double-deficient mice had increased hematpoietic stem cells and displayed medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyper-proliferation and hypo-apoptosis together with enhanced Erk and Akt activation upon cytokine stimulation. Moreover, loss of Dok-1 and/or Dok-2 induced blastic transformation of chronic phase CML-like disease in mice carrying bcr-ab1 gene. These findings demonstrate that Dok-1 and Dok-2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and suppression of leukemia.
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