2004 Fiscal Year Final Research Report Summary
Analysis of the actions and the action mechanism of DIF, an anti-tumor agent isolated from a soil microorganism
| Project/Area Number |
15590123
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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 |
Medical pharmacy
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| Research Institution | Gunma University |
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Principal Investigator |
KUBOHARA Yuzuru Gunma University, Institute for Molecular and Cellular Regulation, Associate Professor, 生体調節研究所, 助教授 (00221937)
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| Co-Investigator(Kenkyū-buntansha) |
KOJIMA Itaru Gunma University, Institute for Molecular and Cellular Regulation, Professor, 生体調節研究所, 教授 (60143492)
HOSAKA Kohei Gunma University, School of Health Sciences, 医学部, 教授 (70108992)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Dictyostelium / DIF-1 / PDE1 / Anti-tumor drug / Erk / K562 / Cancer |
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| Research Abstract |
The cellular slime mould Dictyostelium discoideum is thought to be an excellent model organism for the study of cell and developmental biology because of its simple pattern of development. The differentiation-inducing factor-1(DIF-1) was originally identified as signal molecules that induce stalk cell differentiation in D.discoideum. On the other hand, we have shown that DIF-1 exhibits strong anti-proliferative activities and occasionally induce cell differentiation in mammalian cells. Yet, the mechanisms underlying the actions of DIF-1 in mammalian cells remain to be elucidated.
In the present study, we have shown that ;
1)DIF-1 inactivates STAT3 in gastric cancer cells via MEK/ERK pathway (Kanai et al.2003),
2)DIF-1 inhibits the expression of cyclins D/E and the phosphorylation of retinoblastoma protein (pRb) in K562 cells (Akaishi et al.2004), and
3)calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is a pharmacological and specific target of DIF-1 (Shimizu et al.2004).
4)Furthermore, in order to assess the chemical structure-effect relationship of DIF derivatives and to develop useful agents, we synthesized many analogues of DIF-1 and investigated their stalk-cell-inducing activity anti-proliferative activity in human leukemia K562 cells. We have then found some potent anti-leukemic agents (submitted).
5)During the course of this study, we happened to found that zinc ions inhibit calcineurin activity in vitro (Takahashi et al.2003).
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[Journal Article] Differentiation-inducing factor-1-induced growth arrest of K562 leukemia cells involves the reduction of ERK1/2 activity.2004
Author(s)
Akaishi, E., Narita, T., Kawai, S., Miwa, Y, Sasaguri, T., Hosaka, K., Kubohara, Y.
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Journal Title
Eur.J.Pharmacol. 485
Pages: 21-29
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is a pharmacological target of differentiation-inducing factor-1, an anti-tumor agent isolated from Dictyostelium.2004
Author(s)
Shimizu, K., Murata, T., Tagawa, T., Takahashi, K., Ishikawa, R., Abe, Y, Hosaka, K., Kubohara, Y.
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Journal Title
Cancer Res. 64
Pages: 2568-2571
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Structural requirements of dictyopyrones isolated from Dictyostelium spp. in the regulation of Dictyostelium development and in anti-leukemic activity.2004
Author(s)
Kikuchi, H., Sasaki, K., Sekiya, J., Maeda, Y., Amagai, A., Kubohara, Y., Oshima, Y.
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Journal Title
Bioorg.Med.Chem. 12
Pages: 3203-3214
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Differentiation-inducing factor-1(DIF-1) inhibits STAT3 activity involved in gastric cancer cell proliferation via MEK-ERK dependent pathway.2003
Author(s)
Kanai, M., Konda, Y., Nakajima, T., Izumi, Y, Nanakin, A., Kanda, N., Kubohara, Y., Chiba, T.
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Journal Title
Oncogene 22
Pages: 548-554
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Dictyostelium differentiation-inducing factor-3 activates glycogen synthase kinase-3β and degrades cyclin D1 in mammalian cells.2003
Author(s)
Takahashi-Yanaga, F., Taba, Y., Miwa, Y., Kubohara, Y., Watanabe, Y., Hirata, M., Morimoto, S., Sasaguri, T.
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Journal Title
J.Biol.Chem. 278
Pages: 9663-9670
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Zinc inhibits calcineurin activity in vitro by competing with nickel.2003
Author(s)
Takahashi, N., Akaishi, E., Abe, Y, Ishikawa, R., Tanaka, S., Hosaka, K., Kubohara, Y.
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Journal Title
Biochem.Biophys.Res.Commun. 307
Pages: 64-68
Description
「研究成果報告書概要(欧文)」より
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