Biochemical and Cell Biological Study for Regulators of Notch Signaling
| Project/Area Number |
18590257
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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 |
General medical chemistry
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| Research Institution | Chiba University |
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Principal Investigator |
KITAGAWA Motoo Chiba University, Graduate School of Medicine, Department of Molecular and Tumor Pathology, Associate Professor (40262026)
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| Co-Investigator(Kenkyū-buntansha) |
HARIGAYA Kenichi Chiba University, Graduate School of Medicine, Department of Molecular and Tumor Pathology, Professor (40101894)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,960,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥360,000)
Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2006: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Notch / Mastermind / Signal Transduction / Regulation of Transcription / Development / Hematopoiesis / Abnormal Sex Differentiation / Knockout Mouse / がん |
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| Research Abstract |
Notch signaling has been shown to play an important role in a number of different cell fate decisions. Several loss-of-function studies have revealed that Notch signaling plays an essential role in the multiple developmental stages for hematopoiesis, namely, generation of the definitive hematopoiesis, commitment to T cell fate in the thymus, development from thymic CD4 CD8 double negative (DN) T cells to double positive T cells, and development of splenic marginal zone (MZ) B cells. Previously, we have identified a human Mastermind (Mam) family of proteins, consisting of three members (Mam-1, Mam-2, and Mam-3) and thus elucidated their biochemical mechanisms of action. All of the Mam proteins bind to and stabilize the DNA-binding complex of the intracellular domains of Notch and CSL proteins in the nucleus to activate transcription from target promoters. In this term of project, we have generated a line of Mam-1-deficient mice and found that Mam-1 deficiency abolishes the development of splenic MZB cells, a subset strictly dependent on Notcli2, a CSL protein and Delta 1 ligand. Mam-1 deficiency also causes a partially impaired development of early thymocyres, while not affecting the generation of definitive hematopoiesis, processes that are dependent on Notch1. We also demonstrate the transcriptional activation of a target promoter by constitutively active forms of Notch to decrease severalfold in primarily cultured Mam- 1-deficient cells. These results indicate that Mam-1 is thus required to some extent for Notch-dependent stages in lymphopoiesis, thus supporting the notion that Mam is an essential component of the canonical Notch pathway in mammals.
We also found that the non-canonical Notch target Hes3 promoter can be activated by a product of a gene (MAMLD1) that holds structural similarity with Mam and of which deletion causes hypospadia in humans.
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Report
(3 results)
Research Products
(70 results)
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[Journal Article] Mastermind-like domain containing 1 (MAMLD1 or CXorf6) transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence2008
Author(s)
Fukami M., Wada Y., Okada M., Kato F., Katsumata N., Baba T., Morohashi K.-i., Laporte J., Kitagawa M., and Ogata T.
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Journal Title
J. Biol. Chem. 283
Pages: 5525-5532
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo2007
Author(s)
Oyama T., Harigaya K., Muradil A., Hozumi K., Habu S., Oguro H., Iwama A., Matsuno K., Sakamoto R., Sato M., Yoshida N., and Kitagawa M.
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Journal Title
Proc. Natl. Acad. Sci. U. S. A. 104
Pages: 9764-9769
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Fms-like tyrosine kinase 3 ligand stimulation induces MLL-rearranged leukemia cells into quiescence resistant to antileukemic agents2007
Author(s)
Furuichi Y., Goi K., Inukai T., Sato H., Nemoto A., Takahashi K., Akahane K., Hirose K., Honna H., Kuroda I., Zhang X., Kagami K., Hayashi Y., Harigava K., Nakazawa S., and Sugita K.
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Journal Title
Cancer Res 67
Pages: 9852-9861
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Enhancement of chemosensitivity toward peplomycin by calpastatin -stabilized NF-kB p65 in esophageal carcinoma cells: possible involvement of Fas/Fas-L synergism2006
Author(s)
Liu T.-L., Shimada H., Ochiai T., Shiratori T., Lin S.-E., Kitagawa, M., Harigaya K., Maki M., Oka M., Abe T., Takiguchi M., and Hiwasa T.
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Journal Title
Apoptosis 11
Pages: 1025-1037
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] An essential role of alternative splicing of c-myc suppressor FUSE-binding protein-interacting repressor in carcinogenesis2006
Author(s)
Matsushita K, Tomonaga T., Shimada H., Shioya A., Higashi M., Matsubara H., Harigaya K., Nomura F., Libutti D., Levens D., and Ochiai T.
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Journal Title
Cancer Res 66
Pages: 1409-1417
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo2007
Author(s)
Oyama T., Harigaya K., Muradil A., Hozumi K., Habu S., Oguro H., Iwama A., Matsuno K., Sakamoto R., Sato M., Yoshida N., and Kitagawa M.
Organizer
The 30th Annual Meeting of the Molecular Biology Society of Japan, The 80th Annual Meeting of Japanese Biochemical Society
Place of Presentation
Yokohama
Year and Date
2007-12-15
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Functions of a neurogenicgene, pecanex, in Notch signaling2007
Author(s)
Yamakawa T., Sasamura T., Oyama T., Kanai M., Kitagawa M., Harigaya K., and Matsuno K.
Organizer
The 30th Annual Meeting of the Molecular Biology Society of Japan, The 80th Annual Meeting of Japanese Biochemical Society
Place of Presentation
Yokohama
Year and Date
2007-12-12
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo2007
Author(s)
Kitagawa M., Oyama T., Muradil A., Hozumi K., Habu S., Oguro H., Iwama A., Sakamoto R., Sato M., Yoshida N., and Harigaya K.
Organizer
66th Annual Meeting of the Japanese Cancer Association
Place of Presentation
Yokohama
Year and Date
2007-10-05
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo2007
Author(s)
Oyama T., Harigaya K., Muradil A., Hozumi K., Habu S., Oguro H., Iwama A., Matsuno K., Sakamoto R., Sato M., Yoshida N., and Kitagawa M.
Organizer
The Notch Meeting
Place of Presentation
Athens, Greece
Year and Date
2007-09-26
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo2007
Author(s)
Oyama T., Harigaya K., Muradil A., Hozumi K., Habu S., Oguro H., Iwama A., Hirahara K., Yamashita M., Nakayama T., Sakamoto A., Tokuhisa T., Sakamoto R., Sato M., Yoshida N., and Kitagawa M.
Organizer
The 5th Stem Cell Research symposium
Place of Presentation
Awaji
Year and Date
2007-05-18
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Generation of mice deficient in genes for Mastermind-1 and -2, positive regulators for Notch signaling2006
Author(s)
Oyama T., Harigaya K., Azuma K., Muradil A., Hozumi K., Habu S., Iwama A., Hirahara K., Yamashita M., Nakayama T., Sakamoto A., Tokuhisa T., Sakamoto R., Sato M., Yoshida N., and Kitagawa M.
Organizer
MSBA Forum 2006
Place of Presentation
Nagoya
Year and Date
2006-12-08
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Generation of mice deficient in genes for Mastermind-1 and -2, positive regulators for Notch signaling2006
Author(s)
Oyama T., Harigaya K., Azuma K., Muradil A., Hirahara K., Yamashita M., Nakayama T., Sakamoto A., Tokuhisa T., Sakamoto R., Sato M., Yoshida N., and Kitagawa M.
Organizer
20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
Place of Presentation
Kyoto
Year and Date
2006-06-22
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Generation of mice deficient in genes for Mastermind-1 and -2, positive regulators for Notch signaling2006
Author(s)
Oyama T., Harigaya K., Azuma K., Muradil A., Hirahara K., Yamashita M., Nakayama T., Sakamoto A., Tokuhisa T., Sakamoto R., Sato M., Yoshida N., and Kitagawa M.
Organizer
The 4th Stem Cell Research symposium
Place of Presentation
Tokyo
Year and Date
2006-05-19
Description
「研究成果報告書概要(欧文)」より
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