2004 Fiscal Year Final Research Report Summary
Molecular Mechanisms of Cardiomyocyte Differentiation
| Project/Area Number |
15209025
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Chiba University |
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Principal Investigator |
KOMURO Issei Chiba University, Graduate School of Medicine, Professor, 大学院・医学研究院, 教授 (30260483)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAI Toshio Chiba University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (00334194)
TAKANO Hiroyuki Chiba University, Graduate School of Medicine, Assistant Professor, 大学院・医学研究院, 助手 (60334190)
MINAMINO Tohru Chiba University, University Hospital, Assistant Professor, 医学部附属病院, 助手 (90328063)
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| Project Period (FY) |
2003 – 2004
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| Keywords | cardiomyocytes differentiation / transcriptional regulation / Csx / Nkx2-5 / LIM protein / zinc finger protein / P19Cl6 cell / protein kinase / knockout mice |
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| Research Abstract |
In search for proteins that interact with the cardiac homeobox transcription factor Csx/Nkx2-5, we identified a novel protein Cal (CSX-associated LIM protein) containing LIM domains and Zim1 containing Kruppel-associated box (KRAB) and 11 zinc fingers by using a yeast two-hybrid screening. Csx/Nkx2-5 and Cal associated with each other via the LIM domains of Cal and the homeodomain of Csx/Nkx2-5. Cal itself possessed the transcription-promoting activity, and co-transfection of Cal enhanced Csx/Nkx2-5-induced promoter activation. Cal contained a functional nuclear export signal and shuttled from the cytoplasm into the nucleus in response to calcium. Accumulation of Cal in the nucleus of P19CL6 cells promoted cardiomyocyte differentiation. Zim1 was localized at the nucleus of cardiomyocytes and was associated with N-terminal and homeodomain of Csx/Nkx-2.5 via its zinc fingers. In contrast to Cal, Zim1 suppressed Csx/Nkx-2.5-mediated transcriptional activation, and transient overexpression
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of Zim1 suppressed cardiomyocyte differentiation in P19CL6 cells. These results suggest that transcriptional activity of Csx/Nkx2-5 is regulated by fine-tuned combinatorial interactions with coacitvators such as Cal and corepressors such as Zim1. Furthermore, by differential display technique, we identified a novel protein kinase Midori (myocytic induction/differentiation originator), which is expressed early during cardiogenesis and is involved in cardiomyocyte differentiation of P19CL6 cells. To investigate the developmental function of Midori, we are generating Midori-deficient mice by targeted mutagenesis. A complete null allele of Midori was generated by replacing its first coding exon with a nuclear localization signal-LacZ -pA cassetete followed by a loxP-flanked pgk-neo-pA cassette. Independent 2 lines of ES cells carrying the mutated allele were injected into blastocysts from C57BL/6J mice and the male chimeras were crossed to C57BL/6J mice. We will confirm germ-line transmission, and hererozygous intercross will give rise to offsprings including Midori-deficient mice. Less
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[Journal Article] G-CSF prevents cardiac Remodeling after myocardial infarction by activating Jak/Stat in cardiomyocytes.2005
Author(s)
Harada, M., Qin, Y., Takano, H., Minamino, T., Zou, Y., Toko, H., Ohtsuka, M., Matsuura, K., Sano, M., Nishi, J., Akazawa, H., Kunieda, T., Zhu, W., Hasegawa, H., Kunisada, K., Nagai, T., Nakaya, H., Yamauchi-Takihara, K., Komuro, I.
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Journal Title
Nat Med 11
Pages: 305-311
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway.2004
Author(s)
Miyauchi, H., Minamino, T., Tateno, K., Kunieda, T., Toko, H., Komuro, I.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A novel LIM protein Cal promotes cardiac differentiation by association with CSX/NKX2-5.2004
Author(s)
Akazawa, H., Kudoh, S., Mochizuki, N., Takekoshi, N., Takano, H., Nagai, T., Komuro, I.
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Journal Title
J Cell Biol 164
Pages: 395-405
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Cardiomyocytes fuse with surrounding non-cardiomyocyres and re-enter the cell cycle.2004
Author(s)
Matsuura, K., Wada, H., Nagai, T., Iijima, Y., Minmino, T., Sano, M., Akazawa, H., Molkentin J.D, Kasanuki, H., Komuro, I.
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Journal Title
J Cell Biol 167
Pages: 351-363
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Salt-sensitive hypertension is triggered by Ca(2+) entry via Na(+)/Ca(2+) exchanger type-1 in vascular smooth muscle.2004
Author(s)
Iwamoto, T., Kita, S., Zhang, J., Blaustein, M.P., Arai, Y., Yoshida, S., Wakimoto, K., Komuro, I., Katsuragi, T.
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Journal Title
Nat Med 10
Pages: 1193-1199
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Sox6 regulation of cardiac myocyte development.2003
Author(s)
Cohen-Barak, O., Yi, Z., Hagiwara, N., Monzen, K., Komuro, I., Brilliant, M.H.
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Journal Title
Nucleic Acids Res 31
Pages: 5941-5948
Description
「研究成果報告書概要(欧文)」より
