論文 - 井本　正哉

Cloning and charcterization of DIP1, a novel protein that is related to the Id family of proteins.

Y. Yao, Y. Doki, W. Jiang, V. S. Venkatraj, D. Warburton, R. M. Santella, B. Lu, L. Yan, X-H Sun, T. Su, J. Luo, and I. B. Weinstein.

Exp. Cell Res.  （ 257 ） 22-32 (2000) 2000年06月

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MK800-62F1, a new inhibitor of apoptotic cell death, from Streptomyces diastatochromogenes MK800-62F1. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity

Y. Yoshimoto, T. Sawa, N. Kinoshita, Y. Homma, M. Hamada, T. Takeuchi

Journal of Antibiotics （Journal of Antibiotics）  53 （ 53 ） 569-574 (2000) - 574 2000年06月

研究論文（学術雑誌）, 共著,  ISSN  00218820

　概要を見る

A new compound, MK800-62F1, was isolated from a cultured broth of Streptomyces diastatochromogenes MK800-62F1. It inhibited H2O2-induced apoptosis in human small cell lung carcinoma Ms-1 cells as well as in human T-cell leukemia Jurkat cells. In addition, MK800-62F1 also inhibited camptothecin-induced apoptosis in Jurkat cells, which was mediated by intracellular H2O2 generation. MK800-62F1 did not exhibit antioxidative activity in vitro, suggesting that inhibition of apoptosis by MK800-62F1 was not due to the scavenging of H2O2, rather it was due to the modulation of the downstream event of H2O2 generation.

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MK800-62F1, a new inhibitor of apoptotic cell death, from Streptomyces diastatochromogenes MK800-62F1. II. Structure elucidation

Yoshimoto Y., Sawa T., Naganawa H., Sugai T., Takeuchi T., Imoto M.

Journal of Antibiotics （Journal of Antibiotics）  53 （ 6 ） 575 - 578 2000年06月

研究論文（学術雑誌）, 査読有り,  ISSN  00218820

　概要を見る

A new compound, MK800-62F1, was isolated from a cultured broth of Streptomyces diastatochromogenes MK800-62F1. The structure was determined by NMR analysis and degradation experiments.

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Herbimycin A induces G1 arrest through accumulation of p27(Kip1) in cyclin D1-overexpressing fibroblasts

Endo N., Tashiro E., Umezawa K., Kawada M., Uehara Y., Doki Y., Weinstein I., Imoto M.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications）  267 （ 1 ） 54 - 58 2000年01月

研究論文（学術雑誌）, 査読有り,  ISSN  0006291X

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The ansamycin antibiotic herbimycin A is a potent tyrosine kinase inhibitor and reduces the growth rate of various types of mammalian cells. When quiescent Rat6 fibroblast cells were treated with herbimycin A, serum-induced expression of cyclin D1 was inhibited, and this was associated with inhibition of G1 phase progression. However, herbimycin A also inhibited serum-induced G1 progression in derivatives of the Rat6 fibroblast cell line that stably overexpress a human cyclin D1 cDNA (R6ccnD1 4 cells), without affecting the expression levels of G1 cyclins. We found that herbimycin A prevented serum-induced downregulation of the cyclin-dependent kinase inhibitor p27(Kip1), thereby leading to inactivation of the protein kinase activity of CDK2. These results suggest that herbimycin A inhibits a tyrosine kinase(s) that plays a role in degradation of the p27(Kop1) protein. (C) 2000 Academic Press.

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Cloning and characterization of DIP1, a novel protein that is related to the id family of proteins

Yao Y., Doki Y., Jiang W., Imoto M., Venkatraj V., Warburton D., Santella R., Lu B., Yan L., Sun X., Su T., Luo J., Weinstein I.

Experimental Cell Research （Experimental Cell Research）  257 （ 1 ） 22 - 32 2000年

研究論文（学術雑誌）, 査読有り,  ISSN  00144827

　概要を見る

Using human cyclin D1 as the 'bait' in a yeast two-hybrid system, together with a HL60 cDNA library, we identified a novel human nuclear protein designated DIP1. This protein is expressed in a variety of cell types, and in fibroblasts its level remains constant throughout the cell cycle. However, the level of this protein increases severalfold during the differentiation of HL60 cells. The DIP1 protein can be phosphorylated in vitro by a cellular kinase and this activity reaches its maximum in extracts obtained from cells in the G1 phase of the cell cycle. DIP1 contains a helix- loop-helix motif but lacks an adjacent basic DNA-binding domain, thus resembling the Id family of proteins. The dip1 gene is located on human chromosome 16pl 1.2-12, a locus that is amplified in several types of human cancer. These results suggest that DIP1 may be involved in the control of gene expression and differentiation, but its precise function remains to be determined. (C) 2000 Academic Press.

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Migrastatin, a new inhibitor of tumor cell migration from Streptomyces sp. MK929-43F1 taxonomy, fermentation, isolation and biological activities

Nakae K., Yoshimoto Y., Sawa T., Homma Y., Hamada M., Takeuchi T., Imoto M.

Journal of Antibiotics （Journal of Antibiotics）  53 （ 10 ） 1130 - 1136 2000年

研究論文（学術雑誌）, 査読有り,  ISSN  00218820

　概要を見る

A new compound, migrastatin, was isolated from a cultured broth of Streptomyces sp. MK929-43F1, as an inhibitor of tumor cell migration. It was purified by column chromatographies on silica gel and Sephadex LH-20 and HPLC. Migrastatin has the molecular formula of C27H39NO7 consisting of 14-membered macrolide and glutarimide moiety. It inhibited spontaneous migration of human esophageal cancer EC17 cells. Migration inhibitory activity of migrastatin was not dependent on cytotoxicity or inhibition of protein synthesis.

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Inostamycin, an inhibitor of cytidine 5′-diphosphate 1,2-diacyl-sn-glycerol (CDP-DG): Inositol transferase, suppresses invasion ability by reducing productions of matrix metalloproteinase-2 and -9 and cell motility in HSC-4 tongue carcinoma cell line

Baba Y., Tsukuda M., Mochimatsu I., Furukawa S., Kagata H., Nagashima Y., Sakai N., Koshika S., Imoto M., Kato Y.

Clinical and Experimental Metastasis （Clinical and Experimental Metastasis）  18 （ 3 ） 273 - 279 2000年

研究論文（学術雑誌）, 査読有り,  ISSN  02620898

　概要を見る

Inostamycin is an inhibitor of cytidine 5′-diphosphate 1,2-diacyl-sn-glycerol (CDP-DG): inositol transferase. It significantly reduced epidermal growth factor (EGF)-induced in vitro invasion of the tongue carcinoma cell line, HSC-4, through reconstituted basement membrane Matrigel®. Since phosphatidylinositol (PI) 4,5-biphosphate is important for signal transduction through protein kinase C and actin reorganisation, we further examined the effect of inostamycin on production of two matrix metalloproteinases (MMPs), MMP-2 and -9, and on cell motility. Zymographic analysis showed that inostamycin suppressed pro-MMP-2 and pro-MMP-9 levels at a dose-dependent fashion, while MMP-2 activity was not significantly affected. By reverse transcription-polymerase chain reaction, it was found that inostamycin diminished steady state levels of MMP-2 and -9 but not membrane type 1-MMP mRNA expressions. Inostamycin partially blocked both EGF- and phorbol 12-myristate 13-acetate-stimulated pro-MMP- 9 production. A cytoplasmic calcium chelator (BAPTA-AM) dramatically elevated pro- MMP-9 and slightly elevated pro-MMP-2 secretions. EGF-stimulated motility of HSC-4 cells was suppressed by inostamycin treatment along with reduction of actin cytoskeletal reorganisation, filopodia formation and cdc42 expression. These results suggested that inostamycin would be useful for an anti-invasive agent in tongue cancer.

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Requirement of caspase-3(-like) protease-mediated hydrogen peroxide production for apoptosis induced by various anticancer drugs

清水史郎、高田実、梅沢一夫、井本正哉

Journal of Biological Chemistry （Journal of Biological Chemistry）  273 （ 273 ） 26900 - 26907 1998年10月

研究論文（学術雑誌）, 共著,  ISSN  00219258

　概要を見る

作用機構の異なる種々の制癌剤が共通してカスパーゼ３の活性化、NADPH oxidaseの活性化に伴う過酸化水素の生成という過程をへて、アポトーシスを誘導することを報告した。(8ページ)

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Potentiation of paclitaxel cytotoxicity by inostamycin in human small cell lung carcinoma, Ms-1 cells

清水史郎、田辺圭子、田代悦、高田実、梅沢一夫、井本正哉

Japanese Journal of Cancer Research （Japanese Journal of Cancer Research）  89 （ 89 ） 970 - 976 1998年09月

研究論文（学術雑誌）, 共著,  ISSN  09105050

　概要を見る

イノスタマイシンが小細胞肺癌細胞に対して、タキソールの殺細胞効果を増強することを報告した。(7ページ)

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Caspase-3 activation is not responsible for vinblastine-induced Bcl-2 phosphorylation and G2/M arrest in human small cell lung catcinoma Ms-1 cells.

田代悦、清水史郎、高田実、梅沢一夫、井本正哉

Jpn. J. Cancer Res.  （ 89 ）  1998年09月

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　概要を見る

小細胞肺癌細胞を用いた解析から、ビンブラスチンによるアポトーシスの過程でBcl-2のリン酸化が誘導され、このリン酸化はカスパーゼ3によって阻害されなかった。またビンブラスチンによるG2期停止もカスパーゼ3によって制御されていないことを報告した。(7ページ)

Caspase-3 activation is not responsible for vinblastine-induced Bcl-2 phosphorylation and G2/M arrest in human small cell lung carcinoma Ms-1 cells

Tashiro E., Simizu S., Takada M., Umezawa K., Imoto M.

Japanese Journal of Cancer Research （Japanese Journal of Cancer Research）  89 （ 9 ） 940 - 946 1998年09月

研究論文（学術雑誌）, 査読有り,  ISSN  09105050

　概要を見る

Vinblastine arrests cells in the G2/M phase of the cell cycle and subsequently induces cell death by apoptosis. We found that treatment of cells with vinblastine induced phosphorylation of Bcl-2, resulting in the dissociation of Bcl-2 and Bax. Moreover, vinblastine-induced apoptosis was suppressed by an inhibitor of caspase-3, Ac-DEVD-CHO; and a 17-kDa active fragment of caspase-3 was detected following vinblastine treatment, suggesting that caspase-3 is involved in vinblastine-induced apoptosis. However, Ac-DEVD-CHO affected neither vinblastine-induced Bcl-2 phosphorylation nor vinblastine-induced G2/M arrest. Vinblastine caused G2/M arrest prior to apoptosis, whereas vinblastine-induced apoptosis was not dependent on the duration of the G2/M phase. Thus, vinblastine-induced apoptosis might be mediated by the phosphorylation of Bcl-2, resulting in Bcl-2 inactivation, and by subsequent activation of caspase-3.

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Synthesis of fluorescent substrates for protein tyrosine phosphatase assays

渡辺匠、井本正哉、谷口洋基、木下一彦、梅沢一夫

Bioorganic and Medicinal Chemistry Letters （Bioorganic and Medicinal Chemistry Letters）  8 （ 8 ） 1301 - 1302 1998年08月

研究論文（学術雑誌）, 共著,  ISSN  0960894X

　概要を見る

蛍光標識したチロシンホスファターゼの基質を合成し、簡便なチロシンホスファターゼ測定系を提案した。(2ページ)

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遺伝子の治療への応用　1.癌遺伝子産物(蛋白）を標的とした抗癌剤の開発

井本正哉

臨床消化器内科、  （ 13 ）  1998年07月

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　概要を見る

癌遺伝子産物（蛋白）を標的とした抗癌剤について概説し今後の開発における展望を述べた。(7ページ)

Inhibition of cyclin D1 expression and induction of apoptosis by inostamycin in small cell lung carcinoma cells

井本正哉、田辺圭子、清水史郎、田代悦、高田実、梅沢一夫

Japanese Journal of Cancer Research （Japanese Journal of Cancer Research）  89 （ 89 ） 315 - 322 1998年03月

研究論文（学術雑誌）, 共著,  ISSN  09105050

　概要を見る

ホスファチジルイノシトール代謝回転阻害剤イノスタマイシンが、小細胞肺癌細胞に対して、サイクリンD1の発現を抑制しG1期停止を引き起こし、更にアポトーシスを誘導することを報告した。(8ページ)

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最新の癌治療分子標的 a)細胞周期

井本正哉

化学療法の領域、  （ 14 ）  1998年03月

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　概要を見る

細胞周期を制御する低分子化合物について概説した。(7ページ)

Induction of hydrogen peroxide production and bax expression by caspase- 3(-like) proteases in tyrosine kinase inhibitor-induced apoptosis in human small cell lung carcinoma cells

Simizu S., Umezawa K., Takada M., Arber N., Imoto M.

Experimental Cell Research （Experimental Cell Research）  238 （ 1 ） 197 - 203 1998年01月

研究論文（学術雑誌）, 査読有り,  ISSN  00144827

　概要を見る

In our previous studies (S. Simizu, et al., 1996, Cancer Res. 56, 4978- 4982), we reported that apoptosis of human small cell lung carcinoma (SCLC) cells induced by protein tyrosine kinase inhibitors, such as erbstatin and herbimycin A, was mediated by H2O2 via a newly synthesized protein(s). In the present study, we demonstrated that induction of apoptosis by erbstatin resulted in activation of caspase-3(like) proteases, which are interleukin- 1β-converting enzyme family proteases (caspases) and that inhibition of these protease activities reduced the extent of cell death and H2O2 generation. We also demonstrated that expression of apoptotic protein Bax was induced by erbstatin. Erbstatin-induced Bax expression was inhibited by the inhibitor of caspase-3(-like) proteases. These results indicate that generation of intracellular H2O2 and Bax expression in tyrosine kinase inhibitor-induced apoptosis were modulated by the activation of caspase-3-(- like) proteases in SCLC cells.

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Induction of hydrogen peroxide production and Bax expression by CPP32(-like) proteases in tyrosine kinase inhibitor-induced apoptosis in human small cell lung carcinoma cells.

清水史郎、梅沢一夫、高田実、N. Arber、井本正哉

Exp. Cell Res.  （ 238 ）  1998年01月

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　概要を見る

チロシンキナーゼ阻害剤アーブスタチンによる小細胞肺癌細胞のアポトーシス誘導過程において生成する過酸化水素やBaxの発現はカスパーゼ3によって制御されていることを報告した。(7ページ)

細胞周期を調節する生理活性物質

井本正哉、梅沢一夫

組織培養工学、  （ 23 ）  1997年12月

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　概要を見る

細胞周期を調節する生理活性物質について概説した。(3ページ)

Screening of phosphatidylinositol turnover inhibitors and regulation of cell cycle progression

Umezawa K., Deguchi A., Imoto M.

Japanese Journal of Cancer and Chemotherapy （Japanese Journal of Cancer and Chemotherapy）  24 （ 11 ） 1578 - 1584 1997年11月

研究論文（学術雑誌）, 査読有り,  ISSN  03850684

　概要を見る

Phosphatidylinositol (PI) turnover is considered to be involved in the regulation of cell growth. The enzymes for PI turnover include phospholipase C (PLC), PI4-kinase and PI synthase. We have isolated pholipeptin and fluvirucin B2 from microorganisms and akaterpin from a marine sponge as PLC γ inhibitors. We also isolated echiguanines from Streptomyces as P14-kinase inhibitors. Since echiguanines did not inhibit the enzyme in situ, we synthesized their ribosylated derivatives that were effective in cultured cells. We previously isolated inostamycin from Streptomyces as an inhibitor of PI synthase. We found that inostamycin induced G1 block in cycling NRK cells. Inostamycin inhibited the serum-induced S-phase induction in quiescent NRK cells. Inostamycin was found to decrease serum-induced expression of cyclin D and cyclin E, without inhibiting the activation of MAP kinase. It also inhibited serum-induced activation of CDK2 and phosphorylation of pRB. Thus, PI synthesis was suggested to be involved in regulation of serum- induced S-phase induction by modulating G1 cyclin expression.

Effect of cyclin D1 overexpression on G1- progression related events.

井本正哉、土岐裕一郎、W. Jiang, E. K-H. Han,I.B. Weinstein

Exp. Cell Res.  （ 236 ）  1997年11月

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　概要を見る

サイクリンD1を強制発現させたRat6細胞を用いて、サイクリンD1の過剰発現がもたらすG1期進行の異常の機構を解析した。(8ページ)