| Project/Area Number |
06277101
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
|
| Allocation Type | Single-year Grants |
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
ARAO Ken-ichi Inst. of Medical Science, Univ, of Tokyo, Dept. of Mol. Dev. Biol., Professor, 医科学研究所, 教授 (00012782)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MATSUSHIMA Kouji Faculty of Medicine, Univ, of Tokyo, Dept. of Mol. Preventive Medicine, Professor, 医学部, 教授 (50222427)
NAGATA Shigekazu Osaka Univ. Medical School, Dept. of Genetics, Professor, 医学部, 教授 (70114428)
TAKATSU Kiyoshi Inst. of Medical Science, Univ, of Tokyo, Dept. of Immunology, Professor, 医科学研究所, 教授 (10107055)
MIYAJIMA Atsushi Inst. of Mol. and Cel. Biosciences, Univ, of Tokyo, Lab. of Biosynthesis, Professor, 分子細胞生物学研究所, 教授 (50135232)
TOMIDA Miko Saitama Cancer Center Research Inst., Dept. of Chemotherapy, Senior Researcherpt. of Mol. Dev. Biol., Professor, 主任研究員 (80142115)
溝口 秀昭 東京女子医科大学, 教授 (70049021)
|
|---|
| Project Period (FY) |
1994 – 1998
|
| Project Status |
Completed (Fiscal Year 1998)
|
| Budget Amount *help |
¥222,200,000 (Direct Cost: ¥222,200,000)
Fiscal Year 1997: ¥53,000,000 (Direct Cost: ¥53,000,000)
Fiscal Year 1996: ¥55,200,000 (Direct Cost: ¥55,200,000)
Fiscal Year 1995: ¥53,000,000 (Direct Cost: ¥53,000,000)
Fiscal Year 1994: ¥61,000,000 (Direct Cost: ¥61,000,000)
|
|---|
| Keywords | hemotopoietic stem cells / cytolines / receptors / interleukins / signal transduction / protein kinases / tyrosine phosphorylation / konck-out mouse / プロテインキナーゼ / プロティンキナーゼ / 細胞増殖・分化 / トランスジェニックマウス / チロシンキナーゼ / 転写調節 |
|---|
| Research Abstract |
(1) To elucidate the roles of the cytoplasmic Tyr residues of the hGM-C-SF Rβc, mutational analyses of its Tyr residues were performed by Dr. Arai's group. Fall mutant, in which all Tyr residues were replaced with phenyialanines, can sustain the viability of BA/F3 cells but induces a significantly decreased level of proliferation. Their data suggest that JAK2 plays an important role in the prevention of apoptosis by hGM-CSF. (2)Dr. Nagata's group has identified a myeloid-specific zinc-finger transcription factor (MZF-2). The mMZF-2 protein binds to a DNA element through its zinc-finger domain in the C-terminal domain. When the intact mMZF-2 was cotransfected wills a reporter gene, it did not activate transcription. However, N-terminal deletion mutants greatly enhanced transcription specifically in myeloid cells. Furthermore, in an in vivo competition assay, the middle region of MZF-2 inhibited the mMZF-2-mediated transcription activation, suggesting that mMZF-2 is a transcriptional fac
… More
tor that can specifically work in myeloid cells. (3) Dr. Takatsu's group has investigated that the precise stoichiometory of the hIL-5R subunits and the role of JAK kinase utilized in IL-5 signaling were investigated. IL-5 stimulation resulted in tryrosine phoshporylation of JAK2, JAK1, be and STATS. Moreover, IL-5 induced dimerization of IL-5R subunits caused JAK2 activation and the be phosphorylation, even in the absence of JAK1 activation. Furthermore, tyrosine phosphorylation of JAK1 was found to depend on the activation of JAK2. Detailed study of the C-terminal truncated cytoplasmic domain of IL-5 Ra ,revealed the cytoplasmic stretch at position 346-387, containing the proline-rich region is necessary for JAK2 binding. (4) Dr. Sugiyama's group has performed to prove their hypothesis that the Wilms tumor gene (WT1) has an oncogenic function in hematupoistic progenitor cells. They showed that WT1 competes with differentiation-inducing signal mediated by G-CSF receptor and tranaduces only proliferation signal and thus supported the hypothesis. (5) Dr. Matushima's group has confirmed that human CD34+ and murine Lin-c-kit+ hematopoietic progenitor cells express CCR1 but not IL-8R. Erythroid progenitor cells also express CCR1, and MIP-1a inhibit the proloferation of BFU-E. In vitro culture system which induced DC differentiation was established. Only CDll+hiCD11c+ precursors were able to differentiate into macrophages, indicating that CD11+hiCD11c+and CD11b-/dullCD11c+ cells may represent bifurcated and independent DC differentiation pathways. (6) Dr. Mizoguchi's group has studied the mechanism of megakaryocytic polyploidization by ahuman megakaryocytic cell line , Meg-J. Their data suggested that the polyptoidization process in megakaryocytic cells is associated with transient elevation and subsequent decrease in the cdc2 kinase activity. (7) Mouse Oncostatin M (OSM) gene was cloned by Dr. Miyajima's group as a target gene of STAT5 which is activated by IL-3/GM-CSF. In contrast to human receptors, mouse OSM and LIF do not share the same receptor. Although OSM is expressed in the adult bone marrow, it does not stimulate the bone marrow blood cells. OSM is also expressed in the AGM region of embryos and was found to stimulate the development of blood cells from the AGM region. (8) Using chimeric receptors consisting of the extracellular domain of GM-CSF receptor and the cytopiasmic domain of LIP receptor, Dr. Tomita's group showed that homodimerization of LIF receptor cytoptasmic domain could generate the signals for growth arrest and differentiation in mouse mycloid leukemic cells. Mutational analysis of LIF receptor showed the tight correlation between STAT3 activation and induction of differentiation in the leukemic cells. Less
|
