2001 Fiscal Year Final Research Report Summary
Identification of receptor of anti-tumor factor DIF and development of new DIF-analogs
| Project/Area Number |
11557177
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | Gunma University |
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Principal Investigator |
HOSAKA Kohei Gunma University, Faculty of Medicine, Professor, 医学部, 教授 (70108992)
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| Co-Investigator(Kenkyū-buntansha) |
ADACHI Hiroyuki University of Tokyo, Department of Biotechnology, Associate professor, 大学院・農学生命科学研究科, 助教授 (00211699)
KAWAI Shinjiro Osaka Dental University, Faculty dentistry, Associate professor, 歯学部, 助教授 (70131381)
KOJIMA Itaru Gunma University, Institute for Molecular and Cellular Regulation, Professor, 生体調節研究所, 教授 (60143492)
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| Project Period (FY) |
1999 – 2001
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| Keywords | cellular slime mold / differentiation inducing factor / DIF-1 / calcium / calcineurin / anti-tumor factor / leukemia cells / apotosis |
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| Research Abstract |
1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone (DIF-1) is a stalk-cell-inducing-factor in a slime mold Dictyosterium discoideum. Recently, it was found that DIF-1 exhibits anti-tumor activities and suppresses cell growth in rat pancreatic tumor AR42J cells and that induces erythroid differentiation in human leukemia K562 cells. Furthermore the molecule is known to increase in cytosolic calcium concentration in the cells in the early stage of the treatment. In the present project, we firstly focused no calcineurin (CaN), since this protein plays an important role in the calcium signaling of the cells. DIF-1 and DIF-2 activated CaN in the lower concentration (10-30 nM). But in the higher concentration (10-30 μM) the compounds inhibited the enzyme activity stereo-specifically. These results suggest that CaN is a target protein for DIF. Next we examined the effect DIF-1 no Akt/PKB in K562 cells. The kinase was phosphorylated and potently activated within several hours of incubation with 5-30 μM DIF-1. Calcium-reducing agents TMB-8 and EGTA together with A23187 inhibited the DIF-1 induced activation of Akt/PKB. DIF-1 induced apotosis in insulin secreting insulinoma cells (INS-1) dose-dependently. We found that the apotosis was induced Caspase-independently. We examined the effects of DIF-1 on some bacteria and fungi, and an influenza virus. DIF-1 did not show marked effect no bacteria fungi tested, but it inhibited viral plaque formation in its host MDCK cells in a dose-dependent manner and IC50 was 18.7 μM.
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[Publications] K. Tanaka, H. Adachi, H. Konishi, A. Iwamatsu, K. Ohkawa, T. Shirai, S. Nagata, U. Kikkawa, Y. Fukui: "Identification of protein kinase B (PKB) as a phosphatidylinositol 3,4,5-trisphosphate binding protein in Dictyostelium discoideum"Biosci. Biotechnol. Biochem.. 63. 368-372 (1999)
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