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Gerfelin, a novel inhibitor of geranylgeranyl diphosphate synthase from Beauveria felina QN22047. I. Taxonomy, fermentation, isolation, and biological activities

Zenitani S., Tashiro S., Shindo K., Nagai K., Suzuki K., Imoto M.

Journal of Antibiotics （Journal of Antibiotics） 56 （ 7 ） 617 - 621 2003年08月

研究論文（学術雑誌）, 査読有り, ISSN 00218820

A new compound, gerfelin, was isolated from a culture broth of Beauveria felina QN22047. It was purified by column chromatography on silica gel and by HPLC. Gerfelin has the molecular formula C15H14O6. It inhibited synthesis of geranylgeranyl diphosphate, which was mediated by recombinant human geranylgeranyl diphosphate synthase (hGGPP synthase) in vitro. The inhibitory pattern of gerfelin was noncompetitive against isopentenyl diphosphate, and uncompetitive against farnesyl diphosphate.

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Deletion of the BH1 domain of Bcl-2 accelerates apoptosis by acting in a dominant negative fashion

Kawatani M., Imoto M.

Journal of Biological Chemistry （Journal of Biological Chemistry） 278 （ 22 ） 19732 - 19742 2003年05月

研究論文（学術雑誌）, 査読有り, ISSN 00219258

To investigate the exact biochemical functions by which Bcl-2 regulates apoptosis, we established a stable human small cell lung carcinoma cell line, Ms-1, overexpressing wild-type human Bcl-2 or various deletion and point mutants thereof, and examined the effect of these Bcl-2 mutants on apoptosis induced by antitumor drugs such as camptothecin. Cytochrome c release, caspase-3(-like) protease activation, and apoptosis induced by antitumor drugs were accelerated by overexpression of Bcl-2 lacking a Bcl-2 homology (BH) 1 domain (Bcl-2/ΔBH1), but not by that of BH2, BH3, or BH4 domain-deleted Bcl-2. A similar result was obtained upon the substitution of glycine 145 with alanine in the BH1 domain (Bcl-2/G145A), which failed to interact with either Bax or Bak. Pro-apoptotic Bax and Bak have been known to be activated in response to antitumor drugs, and Bcl-2/G145A as well as Bcl-2/ΔBH1 also accelerated Bax- or Bak-induced apoptosis in HEK293T cells. These two mutants still retained the ability to interact with wild-type Bcl-2 and Bcl-xL, and abrogated the inhibitory effect of wild-type Bcl-2 or Bcl-xL on Bax- or Bak-induced apoptosis. In addition, immunoprecipitation studies revealed that Bcl-2/ΔBH1 and Bcl-2/G145A interrupted the association between wild-type Bcl-2 and Bax/Bak. Taken together, our results demonstrate that Bcl-2/ΔBH1 or Bcl-2/G145A acts as a dominant negative of endogenous anti-apoptotic proteins such as Bcl-2 and Bcl-xL, thereby enhancing antitumor drug-induced apoptosis, and that this dominant negative activity requires both a failure of interaction with Bax and Bak through the BH1 domain of Bcl-2 and retention of the ability to interact with Bcl-2 and Bcl-xL.

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Transmembrane domain of Bcl-2 is required for inhibition of ceramide synthesis, but not cytochrome c release in the pathway of inostamycin-induced apoptosis

Kawatani M., Uchi M., Simizu S., Osada H., Imoto M.

Experimental Cell Research （Experimental Cell Research） 286 （ 1 ） 57 - 66 2003年05月

研究論文（学術雑誌）, 査読有り, ISSN 00144827

Bcl-2 protein plays important roles in the regulation of apoptosis. However, the exact mechanism by which Bcl-2 blocks apoptosis is still unclear. In the present study, we found that overexpression of Bcl-2 in human small cell lung carcinoma Ms-1 cells inhibited not only the release of cytochrome c from mitochondria into cytosol but also de novo ceramide synthesis induced by inostamycin, a phosphatidylinositol turnover inhibitor. To investigate the correlation between the structure of Bcl-2 and its inhibitory function in inostamycin-induced apoptosis, Ms-1 cells that stably overexpress domain-deletional mutants of Bcl-2 were established. Transmembrane domain-deleted Bcl-2 failed to inhibit inostamycin-induced de novo ceramide synthesis, whereas it inhibited inostamycin-induced cytochrome c release, indicating that anchoring of Bcl-2 to membrane was a requirement for its inhibitory effect on inostamycin-induced ceramide synthesis, but not cytochrome c release. Thus, the deletion mutant of tarnsmembrane domain of Bcl-2 can suppress inostamycin-induced apoptosis by inhibiting cytochrome c release, a downstream event of ceramide synthesis in the pathway of inostamycin-induced apoptosis. We also found that the BH3 and BH4 domains of Bcl-2 were necessary for inhibition of inostamycin-induced apoptosis, and deletion of BH1 or BH2 did not affect the inhibitory effect of Bcl-2 to inostamycin-induced apoptotic events. © 2003 Elsevier Science (USA). All rights reserved.

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A novel action of terpendole E on the motor activity of mitotic kinesin Eg5

Nakazawa J., Yajima J., Usui T., Ueki M., Takatsuki A., Imoto M., Toyoshima Y., Osada H.

Chemistry and Biology （Chemistry and Biology） 10 （ 2 ） 131 - 137 2003年02月

研究論文（学術雑誌）, 査読有り, ISSN 10745521

To reveal the mechanism of mitosis, the development of M phase-specific inhibitors is an important strategy. We have been screening microbial products to find specific M phase inhibitors that do not directly target tubulins, and rediscovered terpendole E (TerE) as a novel Eg5 inhibitor. TerE did not affect microtubule integrity in interphase, but induced formation of a monoastral spindle in M phase. TerE inhibited both motor and microtubule-stimulated ATPase activities of human Eg5, but did not affect conventional kinesin from either Drosophila or bovine brain. Although terpendoles have been reported as inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT), the Eg5 inhibitory activity of TerE was independent of ACAT inhibition. Taken together, we demonstrate that TerE is a novel Eg5 inhibitor isolated from a fungal strain.

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Overexpression of cyclin D1 contributes to malignancy by up-regulation of fibroblast growth factor receptor 1 via the pRB/E2F pathway

Tashiro E., Maruki H., Minato Y., Doki Y., Weinstein I., Imoto M.

Cancer Research （Cancer Research） 63 （ 2 ） 424 - 431 2003年01月

研究論文（学術雑誌）, 査読有り, ISSN 00085472

Overexpression of cyclin D1 due to gene rearrangement, gene amplification, or simply increased transcription occurs frequently in several types of human cancers. However, overexpression of cyclin D1 in cell culture system is insufficient, by itself, to cause malignant transformation. In the present study, we found that when rodent fibroblasts that overexpress cyclin D1, but not normal fibroblasts, were treated with basic fibroblast growth factor (bFGF), there was enhanced cell cycle progression, extracellular signal-regulated kinase 2 activation, induction of anchorage-independent growth, and enhanced invasion of a Matrigel barrier. These enhanced responses to bFGF appear to be due to increased expression of fibroblast growth factor receptor 1, at both the mRNA and protein levels, in the cyclin D1-overexpressing cells. We obtained evidence that this increase in fibroblast growth factor receptor 1 expression is mediated through cyclin D1 activation of the pRB/E2F pathway. Taken together, these results suggest that in vivo cyclin D1 overexpression can enhance tumor progression, at least in part, by potentiating the stimulatory efforts of bFGF, which is often produced by stromal cells, and the growth of adjacent tumor cells.

Regulation of FGF receptor-2 expression by transcription factor E2F-1

Tashiro E., Minato Y., Maruki H., Asagiri M., Imoto M.

Oncogene （Oncogene） 22 （ 36 ） 5630 - 5635 2003年

研究論文（学術雑誌）, 査読有り, ISSN 09509232

Fibroblast growth factors (FGF) and their receptors play an important role in cell proliferation, angiogenesis and embryonal development. In this study, we show that expression of the FGF receptor-2 (FGFR-2) protein is induced in the mid-to-late G1 phase of the cell cycle in serum-starved mouse NIH3T3 cells released from starvation. Transcription of mouse FGFR-2 was activated by E2F-1. Analysis of various mouse FGFR-2 promoter mutant constructs showed that a sequence located +57/+64 downstream of the transcriptional initiation site, related to the consensus E2F-responsive sequence, is necessary for the activation. The promoter activity of the mouse FGFR-2 gene is also positively regulated by E2F-2 and E2F-3, but not by E2F-4 and E2F-5. Moreover, the E2F-1-induced activation of mouse FGFR-2 gene transcription is suppressed by pRB. Taken together, the results demonstrate that FGFR-2 is a new class of targets for E2F, and expression of mouse FGFR-2 in mid-to-late G1 phase would be mediated, at least in part, by the activation of a pRB/E2F pathway. © 2003 Nature Publishing Group.

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Vacuolar-type H<sup>+</sup>-ATPase inhibitory activity of synthetic analogues of the concanamycins: Is the hydrogen bond network involving the lactone carbonyl, the hemiacetal hydroxy group, and the C-19 hydroxy group essential for the biological activity of the concanamycins?

Yoshimoto Y., Jyojima T., Arita T., Ueda M., Imoto M., Matsumura S., Toshima K.

Bioorganic and Medicinal Chemistry Letters （Bioorganic and Medicinal Chemistry Letters） 12 （ 24 ） 3525 - 3528 2002年12月

研究論文（学術雑誌）, 査読有り, ISSN 0960894X

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Overexpression of cyclin DI contributes to malignant properties of esophageal tumor cells by increasing VEGF production and decreasing Fas expression

Shintani M., Okazaki A., Masuda T., Kawada M., Ishizuka M., Doki Y., Weinstein I., Imoto M.

Anticancer Research （Anticancer Research） 22 （ 2 A ） 639 - 647 2002年05月

研究論文（学術雑誌）, 査読有り, ISSN 02507005

Cyclin D1 is frequently overexpressed in human esophageal cancer. We examined the possible role of cyclin D1 overexpression on specific malignant properties of tumor cells using a series of eight human esophageal cancer cell lines that express different levels of cyclin D1. We did not find a simple correlation between levels of cyclin D1 expression and anchorage-independent growth, production of angiogenic factors, or tumorigenicity in nude mice, suggesting that other factors can influence these parameters. We did, however, obtain evidence that tumorigenicity appeared to require both the capacity for anchorage-independent growth and the production of angiogenic factors. To better assess the specific role of cyclin D1, we stably expressed an antisense cyclin D1 cDNA construct in the tumorigenic cell line TTn. This significantly decreased anchorage-independent growth and VEGF production and led to a loss of tumorigenicity in nude mice. Furthermore, these cells diplayed a marked increase in sensitivity to antitumor agents and to Fas antibody-induced apoptosis. Taken together, these findings suggest that the overexpression of cyclin D1 can confer esophageal cancer cells with enhanced malignancy through increases in anchorage-independent growth and VEGF production, and down-regulation of Fas expression, thus suggesting novel functions of the cyclin D1 protein in tumor progression.

Absolute configuration of migrastatin, a novel 14-membered ring macrolide.

Nakamura H, Takahashi Y, Naganawa H, Nakae K, Imoto M, Shiro M, Matsumura K, Watanabe H, Kitahara T

The Journal of antibiotics 55 （ 4 ） 442 - 4 2002年04月

研究論文（学術雑誌）, 査読有り, ISSN 0021-8820

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Induction of EGF-dependent apoptosis by vacuolar-type H<sup>+</sup>-ATPase inhibitors in A431 cells overexpressing the EGF receptor

Yoshimoto Y., Imoto M.

Experimental Cell Research （Experimental Cell Research） 279 （ 1 ） 118 - 127 2002年

研究論文（学術雑誌）, 査読有り, ISSN 00144827

The stimulation of human tumor cells overexpressing epidermal growth factor receptor (EGFR) with EGF enhances tumor development and malignancy. Therefore, compounds that modulate the EGF-mediated signal inducing apoptosis in EGFR-overexpressing cells would represent a new class of antitumor drug and might be useful in the treatment of a subset of human tumors. In the course of screening for compounds that induce apoptosis in EGFR-overexpressing human epidermal carcinoma A431 cells from secondary metabolites of microorganisms, we found that vacuolar-type H+-ATPase (V-ATPase) inhibitors, such as concanamycin B and destruxin E, induced apoptosis only when the cells were stimulated with EGF. The EGF-dependent apoptosis by V-ATPase inhibitors was not observed in other types of human tumor cells which do not overexpress EGFR. The apoptosis in A431 cells was inhibited by anti-FasL antibody which neutralized the cytotoxic effect of FasL, indicating that the Fas/FasL system was involved. The expression of cell surface FasL was upregulated by stimulation with EGF and increased further by V-ATPase inhibitors. Moreover, EGF inhibited cytotoxic Fas antibody-induced apoptosis, whereas V-ATPase inhibitors disrupted the protective effect of EGF on apoptosis in A431 cells. Taken together, these results suggested that V-ATPase inhibitors induced EGF-dependent apoptosis in A431 cells, possibly through both the enhancement of EGF-induced cell surface expression of FasL and the disruption of an EGF-induced survival signal. © 2002 Elsevier Science (USA).

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Study of the novel compounds modulating signal transduction system from microbial origin

Imoto M.

Japanese Journal of Antibiotics （Japanese Journal of Antibiotics） 54 （ 3 ） 117 - 125 2001年05月

研究論文（学術雑誌）, 査読有り, ISSN 03682781

微生物由来細胞内情報伝達系に作用する物質の探索研究.

Jpn. J. Antibiot. （ 54 ） 117-125 (2001) 2001年03月

単著

バイオの窓「大学における物取り研究」

バイオサイエンスとインダストリー（ 59 ） 43(2000) 2001年03月

単著

Cytostatic effect of inostamycin, an inhibitor of cytidine 5′-diphosphate 1,2-diacyl-sn-glycerol (CDP-DG): Inositol transferase, on oral squamous cell carcinoma cell lines

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

Cell Biology International （Cell Biology International） 25 （ 7 ） 613 - 620 2001年

研究論文（学術雑誌）, 査読有り, ISSN 10656995

Inostamycin, which was recently isolated from Streptomyces sp. MH816-AF15 as an inhibitor of cytidine 5′-diphosphate 1,2-diacyl-sn-glycerol (CDP-DG): inositol transferase, caused a G1-phase accumulation in the cell cycle of small cell lung carcinomas. To investigate whether the cytostatic effect of inostamycin is restricted to lung carcinoma cell lines or applicable to other type of cells, we tested five oral squamous cell carcinoma (SCC) cell lines. Cell growth was suppressed in 62.5-125 ng/ml inostamycin in the culture medium in all oral cancer cell lines tested, with non-viable cells being < 1%, indicating inostamycin is cytostatic on SCC cell lines. Decrease in cyclin D1 mRNA and protein expression due to the inostamycin treatment was accompanied by suppression of phosphorylated retinoblastoma susceptibility gene product (pRB-P) levels. Moreover, flow cytometric analysis showed that inostamycin induced an increase in G1/G0 cells (1.2-3.2 fold) over 24 h. These results suggest that inostamycin is a useful agent for tumour dormant cytostatic therapy for oral SCC. © 2001 Academic Press.

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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.

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

Clinical and Experimental Metastasis （ 18 ） 273-279 (2000) 2000年12月

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Migrastatin, a novel 14-membered lactone from Streptomyces sp. MK929-43F1.

K. Nakae, Y. Yoshimoto, M. Ueda, T. Sawa, Y. Takahashi, H. Naganawa

J. Antibiot. （ 53 ） 1228-1230 (2000) 2000年11月

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Migrastatin, a new inhibitor of tumor cell migration from Streptomyces sp. MK929-43F1.

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

J. Antibiot. （ 53 ） 1130-1136 (2000) 2000年11月

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Bcl-2-independent induction of apoptosis by neuropeptide receptor antagonist in human small cell lung carcinoma cells

Y. Matsumoto, M. Kawatani, S. Simizu, T. Tanaka, M. Takada

Anticancer Research （Anticancer Research） 20 （ 20 ） 3123-3130 (2000) - 3129 2000年08月

研究論文（学術雑誌）, 共著, ISSN 02507005

The broad-spectrum antagonist of neuropeptide receptor, [D-Arg1, D-Phe5, D-Trp7,9, Leu17]substance P, induced apoptosis selectively in human small cell lung carcinoma (SCLC) cells, which express gastrin-releasing peptide receptor, but not in other types of tumor cells as well as normal cells. The addition of gastrin-releasing peptide or bombesin and the inhibitor of caspase-3 suppressed [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P-induced apoptosis. Moreover, [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P-induced apoptosis was not suppressed by Bcl-2 over-expression. Thus, blockage of gastrin-releasing peptide receptor-mediated signaling may provide a novel therapeutic option in SCLC which has become resistant to conventional chemotherapeutic agents.

Involvement of protein kinase C-regulated ceramide generation in inostamycin-induced apoptosis

M. Kawatani, S. Simizu, H. Osada, M. Takada, N. Arber

Experimental Cell Research （Experimental Cell Research） 259 （ 259 ） 389-397(2000) - 397 2000年07月

研究論文（学術雑誌）, 共著, ISSN 00144827

Activation of caspases is commonly involved in the apoptosis induced by various anticancer drugs. However, the upstream events leading to the activation of caspases seem to be specific to each anticancer drug. In the present study, we examined the possible involvement of protein kinase C (PKC) and ceramide generation in caspase-3(-like) protease activation induced by inostamycin, a phosphatidylinositol synthesis inhibitor. Treatment of cells with 12-O-tetradecanoyl phorbol-13-acetate (TPA), an activator of PKC, suppressed the release of cytochrome c from mitochondria and the activation of caspase-3(-like) proteases in inostamycin-treated cells, but not in other anticancer drug-treated cells. Inostamycin induced the elevation of intracellular ceramide levels, and fumonisin B1, an inhibitor of ceramide synthase, inhibited inostamycin-induced cytochrome c release, caspase-3(-like) protease activation, and apoptosis. Moreover, TPA also inhibited inostamycin-induced ceramide synthesis. Taken together, our results suggest that inostamycin-induced apoptosis is mediated by PKC-regulated ceramide generation, leading to the activation of a caspase cascade. (C) 2000 Academic Press.

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MK800-62F1, a new inhibitor of apoptotic cell death, from Streptomyces diastatochromogenes MK800-62F1. II. Structure elucidation. J. Antibiot. 53, 575-578 (2000)

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

J. Antibiot. （ 53 ） 575-578 (2000) 2000年06月

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