論文 - 井本　正哉

Synthesis and antitumor activity of combretastatin D-4

Uno K., Tanabe T., Ogamino T., Okada R., Imoto M., Nishiyama S.

Heterocycles （Heterocycles）  75 （ 2 ） 291 - 296 2008年02月

研究論文（学術雑誌）, 査読有り,  ISSN  03855414

　概要を見る

Combretastatin D-4 1 was synthesized using electrochemical dimerization of phenols as the key step. Anodic oxidation of bromochloro-phenol 7 provided the corresponding diaryl ether 8. Manipulation of the two hydroxyl groups differenciated, provided the seco-acid, which on Mitsunobu reaction gave the target molecule. Its biological assay showed new potent inhibitory activity against cellular proliferation of human HT-29 colon carcinoma cells. © 2008 The Japan Institute of Heterocyclic Chemistry.

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Transcriptional regulation of a new variant of human platelet-derived growth factor receptor α transcript by E2F-1

Minato Y., Tashiro E., Kanai M., Nihei Y., Kodama Y., Imoto M.

Gene （Gene）  403 （ 1-2 ） 89 - 97 2007年11月

研究論文（学術雑誌）, 査読有り,  ISSN  03781119

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Platelet-derived growth factors (PDGFs) and their receptors play an important role in cell proliferation, angiogenesis, and differentiation during normal development, and have also been implicated in tumorigenesis. In this study, we identified a novel variant of human PDGF receptor α mRNA (type II), which contains the same open reading frame as the known PDGF receptor α mRNA (type I) but a different 5′-untranslated region (5′-UTR). The 5′-UTR of the type II transcript was identified as a 363-bp exon located in intron 1 at position + 1210 to + 1572 relative to the transcriptional initiation site of the type I transcript. This type II transcript was expressed in a subset of human cell lines, such as MG-63 and MNNG/HOS cells. Moreover, transcription of the type II, but not the type I, was regulated by E2F-1 through an E2F-1-responsive site located at position + 1086/+ 1093 downstream of the transcriptional initiation site of the type I transcript. Furthermore, epigenetic modulation might be involved in the expression of the type II transcript. Our findings provide new insights into the regulatory mechanism of PDGF receptor α transcription in normal and tumor cells. © 2007 Elsevier B.V. All rights reserved.

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[Development of farnesyltransferase inhibitor for anti-cancer drugs].

Takemoto Y, Imoto M

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 52 （ 13 Suppl ） 1713 - 8 2007年10月

研究論文（学術雑誌）, 査読有り,  ISSN  0039-9450

Development of farnesyltransferase inhibitor for anti-cancer drugs

Takemoto Y., Imoto M.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme （Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme）  52 （ 13 Suppl ） 1713 - 1718 2007年10月

研究論文（学術雑誌）, 査読有り,  ISSN  00399450

Trierixin, a novel inhibitor of ER stress-induced XBP1 activation from Streptomyces sp. I. Taxonomy, fermentation, isolation, and biological activities

Tashiro E., Hironiwa N., Kitagawa M., Futamura Y., Suzuki S., Nishio M., Imoto M.

Journal of Antibiotics （Journal of Antibiotics）  60 （ 9 ） 547 - 553 2007年09月

研究論文（学術雑誌）, 査読有り,  ISSN  00218820

　概要を見る

In the course of screening for an inhibitor of ER stress-induced XBP1 activation, we isolated a new member of the triene-ansamycin group compound, trierixin, from a culture broth of Streptomyces sp. AC 654. Trierixin was purified by column chromatography on silica gel and by HPLC. The molecular formula of trierixin is C37H52N2O8S. Trierixin inhibited thapsigargin-induced XBP1-luciferase activation in HeLa/XBP1-luc cells and endogenous XBP1 splicing in HeLa cells with an IC 50 of 14 ng/ml and 19 ng/ml, respectively. Moreover, in the process of isolating trierixin, we isolated structurally related mycotrienin II and trienomycin A as inhibitors of ER stress-induced XBP1 activation from a culture broth of a trierixin-producing strain. This study provides the first observation that triene-ansamycins have a novel inhibitory effect against XBP1 activation. © Japan Antibiotics Research Association.

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Trierixin, a novel inhibitor of ER stress-induced XBP1 activation from Streptomyces sp. II. Structure elucidation

Futamura Y., Tashiro E., Hironiwa N., Kohno J., Nishio M., Shindo K., Imoto M.

Journal of Antibiotics （Journal of Antibiotics）  60 （ 9 ） 582 - 585 2007年09月

研究論文（学術雑誌）, 査読有り,  ISSN  00218820

　概要を見る

Trierixin, a new member of the triene-ansamycin group, has been isolated from the fermentation broth of Streptomyces sp. AC654 as an inhibitor of ER stress-induced XBP1 activation. The structure of trierixin was determined on the basis of its spectroscopical and chemical properties. Trierixin possessed a 21-membered macrocyclic lactam, which contains a methylthio-benzenediol structure, and a cyclohexanecarbonylalanine moiety. Trierixin is thus elucidated as 21-thiomethylmycotrienin II. © Japan Antibiotics Research Association.

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Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression

Tashiro E., Tsuchiya A., Imoto M.

Cancer Science （Cancer Science）  98 （ 5 ） 629 - 635 2007年05月

研究論文（学術雑誌）, 査読有り,  ISSN  13479032

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Cyclin D1 binds to the Cdk4 and Cdk6 to form a pRB kinase. Upon phosphorylation, pRB loses its repressive activity for the E2F transcription factor, which then activates transcription of several genes required for the transition from the G1- to S-phase and for DNA replication. The cyclin D1 gene is rearranged and overexpressed in centrocytic lymphomas and parathyroid tumors and it is amplified and/or overexpressed in a major fraction of human tumors of various types of cancer. Ectopic overexpression of cyclin D1 in fibroblast cultures shortens the G1 phase of the cell cycle. Furthermore, it has been demonstrated that introduction of an antisense cyclin D1 into a human carcinoma cell line, in which the cyclin D1 gene is amplified and overexpressed, causes reversion of the malignant phenotype. Thus, increased expression of cyclin D1 can play a critical role in tumor development and in maintenance of the malignant phenotype. However, it is insufficient to confer transformed properties on primary or established fibroblasts. In this review, we summarize the role of cyclin D1 on tumor development and malignant transformation. In addition, our chemical biology study to understand the regulatory mechanism of cyclin D1 transcription is also reviewed. © 2007 Japanese Cancer Association.

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Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

Tsuchiya A., Tashiro E., Yoshida M., Imoto M.

Oncogene （Oncogene）  26 （ 11 ） 1522 - 1532 2007年03月

研究論文（学術雑誌）, 査読有り,  ISSN  09509232

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Leptomycin B (LMB) is a Streptomyces metabolite that causes the specific inhibition of the nuclear export of proteins containing a nuclear export signal (NES). LMB was reported to inhibit cell cycle progression in fission yeast and mammalian cells, however, the mechanism underlying LMB-induced cell cycle arrest is still obscure. In this study, we found that in serum-starved NIH3T3 cells, LMB inhibited serum-induced cyclin D1 expression at the level of transcription. However, this inhibition was reversed by inhibitors of protein phosphatase 2A (PP2A). Furthermore, we found that PP2A accumulated in the nucleus upon treatment with LMB. The finding prompted us to identify the functional NES in PP2A catalytic subunit α. These results indicated that LMB inhibited the chromosomal region maintenance 1 (CRM1)-dependent nuclear export of PP2A, resulting in sustained dephosphorylation in the nucleus. Although phosphorylation of c-Jun at Ser-63 is required for activator protein 1 (AP-1)-dependent expression of cyclin D1, it decreased in LMB-treated cells compared to untreated cells. Moreover, the inhibitors of PP2A restored the levels of c-Jun phosphorylated at Ser-63. We propose that inhibition of cyclin D1 expression by LMB is mediated by the LMB-induced nuclear accumulation of PP2A, leading to sustained dephosphorylation of c-Jun at Ser-63, which leads to inactivation of the transcription of the AP-1-responsive cyclin D1 gene. © 2007 Nature Publishing Group All rights reserved.

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Synthesis of gerfelin and related analogous compounds

Islam M., Kitagawa M., Imoto M., Kitahara T., Watanabe H.

Bioscience, Biotechnology and Biochemistry （Bioscience, Biotechnology and Biochemistry）  70 （ 10 ） 2523 - 2528 2006年11月

研究論文（学術雑誌）, 査読有り,  ISSN  09168451

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Gerfelin, an inhibitor of human geranylgeranyl diphosphate (GGPP) synthase that has been isolated from a culture broth of Beauveria felina QN22047, was synthesized in 4 and 3 steps starting from 2,4-dihydroxy-6-methylbenzoic acid and 3,4,5-trihydroxytoluene, respectively. An effective ligand, 2-(di-tert-butyl-phosphino) biphenyl, was used in the palladium-catalyzed diaryl ether-forming reaction. Five analogous compounds of gerfelin were also synthesized for a study of the structure-activity relationship.

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The education system for chemical biology in Japanese universities.

Osada H., Hagiwara M., Toshima K., Imoto M.

ACS chemical biology （ACS chemical biology）  1 （ 8 ） 492 - 494 2006年09月

研究論文（学術雑誌）, 査読有り,  ISSN  1554-8929

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Suppression of multidrug resistance by migrastatin

Takemoto Y., Tashiro E., Imoto M.

Journal of Antibiotics （Journal of Antibiotics）  59 （ 7 ） 435 - 438 2006年07月

研究論文（学術雑誌）, 査読有り,  ISSN  00218820

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Migrastatin (MGS) is a Streptomyces metabolite that inhibits cancer cell migration. In this study, we found that MGS also enhanced the cytotoxicity of vinblastine, vincristine, and taxol in P-glycoprotein-overexpressing VJ-300 cells and P388/VCR cells. Furthermore, MGS increased the intracellular concentration of labeled vinblastine, vincristine, and taxol in both VJ-300 cells and P388/VCR cells. P-glycoprotein was photolabeled with [ 3H]azidopine, but this photolabeling was significantly inhibited in the presence of MGS. These results indicated that MGS directly interacts with and inhibits P-glycoprotein, thereby sensitizing drug-resistant cells to anticancer drugs. © Japan Antibiotics Research Association.

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Synthesis of verbenachalcone congeners and their biological assessment against activation of the NGF-mediated neurite outgrowth of PC12D cells' activity

Tanabe T., Ogamino T., Shimizu Y., Imoto M., Nishiyama S.

Bioorganic and Medicinal Chemistry （Bioorganic and Medicinal Chemistry）  14 （ 8 ） 2753 - 2762 2006年04月

研究論文（学術雑誌）, 査読有り,  ISSN  09680896

　概要を見る

Synthesis of the verbenachalcone derivatives 3-5 involving littorachalcone 2 from diaryl ether 7 enabled an SAR study of enhancement activity against the NGF-mediated neurite outgrowth from PC12D cells. Littorachalcone 2 and o-deoxyverbenachalcone 5 showed similar activity to that of verbenachalcone 1. © 2005 Elsevier Ltd. All rights reserved.

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GSK-3β directly phosphorylates and activates MARK2/PAR-1

Kosuga S., Tashiro E., Kajioka T., Ueki M., Shimizu Y., Imoto M.

Journal of Biological Chemistry （Journal of Biological Chemistry）  280 （ 52 ） 42715 - 42722 2005年12月

研究論文（学術雑誌）, 査読有り,  ISSN  00219258

　概要を見る

In Alzheimer disease (AD), the microtubule-associated protein tau is found hyperphosphorylated in paired helical filaments. Among many phosphorylated sites in tau, Ser-262 is the major site for abnormal phosphorylation of tau in AD brain. The kinase known to phosphorylate this particular site is MARK2, whose activation mechanism is yet to be studied. Our first finding that treatment of cells with LiCl, a selective inhibitor of another major tau kinase, glycogen synthase kinase-3β (GSK-3β), inhibits phosphorylation of Ser-262 of tau led us to investigate the possible involvement of GSK-3β in MARK2 activation. In vitro kinase reaction revealed that recombinant GSK-3β indeed phosphorylates MARK2, whereas it failed to phosphorylate Ser-262 of tau. Our further findings led us to conclude that GSK-3β phosphorylates MARK2 on Ser-212, one of the two reported phosphorylation sites (Thr-208 and Ser-212) found in the activation loop of MARK2. Down-regulation of either GSK-3β or MARK2 by small interfering RNAs suppressed the level of phosphorylation on Ser-262. These results, respectively, indicated that GSK-3β is responsible for phosphorylating Ser-262 of tau through phosphorylation and activation of MARK2 and that the phosphorylation of tau at this particular site is predominantly mediated by a GSK-3β-MARK2 pathway. These findings are of interest in the context of the pathogenesis of AD. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

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Chemistry and biology of moverastins, inhibitors of cancer cell migration, produced by Aspergillus

Takemoto Y., Watanabe H., Uchida K., Matsumura K., Nakae K., Tashiro E., Shindo K., Kitahara T., Imoto M.

Chemistry and Biology （Chemistry and Biology）  12 （ 12 ） 1337 - 1347 2005年12月

研究論文（学術雑誌）, 査読有り,  ISSN  10745521

　概要を見る

Cancer cell migration is a required step in cancer metastasis. We screened for inhibitors of cancer cell migration of microbial origin, and obtained moverastin, a member of the cylindrol family, from Aspergillus sp. F7720. However, the results of an NMR spectroscopic analysis raised the possibility that moverastin is a mixture of two diastereomers. Separation of the C-10 epimers of synthetic moverastin and a bioassay revealed that both diastereomers (moverastins A and B) had inhibitory effects on cell migration. Furthermore, we demonstrated that moverastins A and B inhibited FTase in vitro, and they also inhibited both the membrane localization of H-Ras and the activation of the PI3K/Akt pathway in EC17 cells. Thus, moverastins inhibited the migration of tumor cells by inhibiting the farnesylation of H-Ras, and subsequent H-Ras-dependent activation of the PI3K/Akt pathway. ©2005 Elsevier Ltd All rights reserved.

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Involvement of nuclear accumulation of heat shock protein 27 in leptomycin B-induced apoptosis in HeLa cells

Tsuchiya A., Tashiro E., Yoshida M., Imoto M.

Journal of Antibiotics （Journal of Antibiotics）  58 （ 12 ） 810 - 816 2005年12月

研究論文（学術雑誌）, 査読有り,  ISSN  00218820

　概要を見る

Leptomycin B (LMB) is a Streptomyces metabolite that inhibits the chromosomal region maintenance (CRM)1-dependent nuclear export of proteins. It also induces apoptosis in several types of cancer cells, by a yet undefined mechanism. We used a functional proteomics approach to delineate the pathways and mediators involved in LMB-induced apoptosis in HeLa cells. Using two-dimensional gel electrophoresis, we searched for proteins accumulated in the nuclei of HeLa cells upon LMB treatment. Among such proteins we found prohibitin and Heat shock protein (Hsp)27, identified by peptide mass fingerprinting and mass spectrometry. Immunocytochemistry was carried out to confirm the LMB-induced nuclear accumulation of these two proteins in HeLa cells. Furthermore, we found that the cytoplasmic expression of Hsp27, but not prohibitin, partially inhibited LMB-induced apoptosis, indicating that nuclear sequestration of Hsp27 was, at least in part, involved in the apoptosis. © Japan Antibiotics Research Association.

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Mutational analysis of growth arrest and cellular localization of human immunodeficiency virus type 1 Vpr in the budding yeast, Saccharomyces cerevisiae

Nakazawa J., Watanabe N., Imoto M., Osada H.

Journal of General and Applied Microbiology （Journal of General and Applied Microbiology）  51 （ 4 ） 245 - 256 2005年10月

研究論文（学術雑誌）, 査読有り,  ISSN  00221260

　概要を見る

Viral protein R (Vpr), one of the accessory gene products of human immunodeficiency virus type 1 (HIV-1), is responsible for the incorporation of a viral genome into the nucleus upon infection. Vpr also arrests the cell cycle and induces apoptosis in infected cells. Similarly, in yeast, Vpr localizes in the nucleus and shows growth inhibitory activity; however, the molecular mechanism of growth inhibition remains unknown. To elucidate this mechanism, several point mutations of Vpr, which are known to perturb several phenotypes of Vpr in mammalian cells, were introduced in the budding yeast, Saccharomyces cerevisiae. For the first time, we found that growth inhibition by Vpr occurred independently of intracellular localization in yeast, as has previously been reported in mammals. We also indentified several amino acid residues, the mutation of which cancels growth inhibitory activity, and/or alters localization, both in yeast and mammalian cells, suggesting the importance of these residues for the phenotypes. Copyright © 2005 by The Microbiology Research Foundation.

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[Regulation of tumor malignancy by inhibitors of posttranslational modification of Ras and Rho family proteins].

Imoto M

Seikagaku. The Journal of Japanese Biochemical Society 77 （ 6 ） 511 - 8 2005年06月

研究論文（学術雑誌）, 査読有り,  ISSN  0037-1017

Regulation of tumor malignancy by inhibitors of posttranslational modification of Ras and Rho family proteins

Imoto M.

Seikagaku. The Journal of Japanese Biochemical Society （Seikagaku. The Journal of Japanese Biochemical Society）  77 （ 6 ） 511 - 518 2005年06月

研究論文（学術雑誌）, 査読有り,  ISSN  00371017

Synthesis of the naphthalene-derived inhibitors against Cdc25A dual-specificity protein phosphatase and their biological activity

Shimbashi A., Tsuchiya A., Imoto M., Nishiyama S.

Bioorganic and Medicinal Chemistry Letters （Bioorganic and Medicinal Chemistry Letters）  15 （ 1 ） 61 - 65 2005年01月

研究論文（学術雑誌）, 査読有り,  ISSN  0960894X

　概要を見る

The synthesis naphthoquinones exhibited stronger activity than the pyranonaphthoquinone-type compound having moderate inhibitory activity against Cdc25A protein phosphatase. The novel naphthalene-type analogues 14 and 18 and the naphthoquinone-type analogues, 8, 9, 15, 16, 19, 21, 22, and 23-28 have been synthesized, and their in vitro Cdc25A phosphatase-inhibitory activity was examined. In assessment of the inhibitory activity, it was revealed that the naphthoquinone core is contributed to the activity, rather than the alkyl side chain. © 2004 Elsevier Ltd. All rights reserved.

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The synthesis and biological activity of pyranonaphthoquione derivatives from Streptomyces sp. and their related substances

Shimbashi A., Tsuchiya A., Imoto M., Nishiyama S.

Bulletin of the Chemical Society of Japan （Bulletin of the Chemical Society of Japan）  77 （ 10 ） 1925 - 1930 2004年10月

研究論文（学術雑誌）, 査読有り,  ISSN  00092673

　概要を見る

The total synthesis of a novel pyranonaphthoquinone (2) having Cdc25A phosphatase inhibitory activity is achieved. The key step in this synthetic pathway is the intramolecular Michael addition for construction of the pyran ring system. The inhibitory activity of several derivatives, readily obtained from synthetic intermediates of 2, is assessed. The resulting data indicates that the pyran ring moiety is not a crucial factor for the activity.

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