Papers - Imoto, Masaya

Effects of cyclin D1 overexpression on G1 progression-related events

Imoto M., Doki Y., Jiang W., Han E., Weinstein I.

Experimental Cell Research (Experimental Cell Research)  236 ( 1 ) 173 - 180 1997.10

Research paper (scientific journal), Accepted,  ISSN  00144827

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In previous studies (W. Jiang, S.M. Kahn, P. Zhou, Y.-J. Zhang, A.M. Cacace, A.S. Infance, Y. Doi, R.M. Santella, and I.B. Weinstein 1993, Oncogene 8, 3447-3457) we reported that stable overexpression of cyclin D1 in R6 rat embryo fibroblasts shortens the G1 phase and impairs growth control. In the present study we examined the effects of cyclin D1 overexpression on other events involved in the G1 to S progression, utilizing the overexpressor cell line R6-ccnD1. We found that when compared to R6 control cells, serum- starved quiescent R6-ccnD1 cells had not only increased levels of the cyclin D1 protein but also increased levels of the cyclin E protein. The latter protein was complexed to phosphorylated cyclin-dependent kinase 2 (CDK2). However, in quiescent serum-starved R6-ccnD1 cells this cyclin E-CKD2 complex lacked in vitro kinase activity due to the presence of a heat-stable inhibitory activity, apparently reflecting the inhibitory effects of the CDK inhibitors (CDK1s) p21(WAF1) and p27(KIP1). Serum stimulation of the quiescent R6-ccnD1 cells was associated with a loss of this inhibitory activity and a decrease in the levels of the latter two proteins, as the cells progressed through the G1 phase. On the other hand, serum stimulation of the control R6 cells was associated with both induction of cyclin E and increased levels of phosphorylated CDK2 proteins and decreased levels of p21(WAF1) and p27(KIP1), as the cells progressed through the G1 phase. Thus, even though over-expression of cyclin D1 can induce the expression of cyclin E and phosphorylated CDK2, premature activation of cyclin E-CDK2 kinase activity in quiescent cells or during progression through G1 appears to be blocked by CDK1s. Nevertheless, the R6ccnD1 cells have a shorter G1 phase than the control cells presumably due to the high levels of both cyclin D1 and cyclin E. Taken together, these results indicate that overexpression of cyclin D, which is frequently seen in human tumors, can have complex effects on the expression of other genes that control cell cycle progression.

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細胞周期と抗がん剤

吉田稔、井本正哉、堀之内末治

BIO Clinica  ( 12 )  1997.10

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抗癌剤の細胞周期に及ぼす影響について概説した。(4ページ)

Enhancement or induction of neurite formation by a protein tyrosine phosphatase inhibitor, 3,4-dephostatin, in growth factor-treated PC12h cells

Fujiwara S., Watanabe T., Nagatsu T., Gohda J., Imoto M., Umezawa K.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  238 ( 1 ) 213 - 217 1997.09

Research paper (scientific journal), Accepted,  ISSN  0006291X

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We studied the effect of the 3,4 dihydroxy analogue of dephostatin (3,4-dephostatin), an inhibitor of protein-tyrosine phosphatase (PTPase), on the differentiation of rat pheochromocytoma PC12 cells. 3,4-Dephostatin accelerated NGF-induced neurite formation in PC12h cells, a subline of PC12 cells, whereas the inhibitor alone did not induce neurite formation. It sustained the NGF-induced tyrosine phosphorylation of several proteins, most prominently that of mitogen-activated protein (MAP) kinase. EGF alone did not induce differentiation in PC12h cells, but it induced neurite formation in the presence of 3,4-dephostatin. The inhibitor also prolonged EGF-induced tyrosine phosphorylation and activation of MAP kinase. An inactive analogue of dephostatin, 2'-O-methyl-dephostatin showed no effect on either neurite formation or MAP kinase tyrosine phosphorylation in NGF- or EGF-treated PC12h cells. Thus, we demonstrated that the PTPase inhibitor could enhance growth factor-induced differentiation in PC12 cells possibly by sustaining the MAP kinase activity.

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Enhancement or induction of neurite formation by a protein tyrosine phosphatase inhibitor, 3,4- dephostatin, in growthfactor-treated PC12 cells.

藤原聰鯉、渡辺匠、長津利治、合田仁、井本正哉、梅沢一夫

Biochem. Biopys. Res. Commun.,  ( 238 )  1997.09

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チロシンホスファターゼ阻害剤デフォスタチンの誘導体がNGFによるPC12細胞の神経突起伸長を促進したことをを報告した。(5ページ)

イノシトール代謝回転阻害剤と細胞周期の制御

梅沢一夫、出口敦子、井本正哉

癌と化学療法、  ( 24 )  1997.09

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イノシトールリン脂質代謝回転阻害剤の細胞周期に及ぼす影響について概説した。(7ページ)

Increased expression of the p27KIP1 protein in human esophageal cancer cell lines that over- epress cyclin D1.

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

Carcinigenesis  ( 18 )  1997.06

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ヒト食道癌において、サイクリンD1の過剰発現が観察されるが、サイクリンD1の過剰発現は、同時にp27Kip1の発現も上昇することを報告した。(10ページ)

Increased expression of the p27(KIP1) protein in human esophageal cancer cell lines that over-express cyclin D1

Doki Y., Imoto M., Han E., Sgambato A., Weinstein I.

Carcinogenesis (Carcinogenesis)  18 ( 6 ) 1139 - 1148 1997.06

Research paper (scientific journal), Accepted,  ISSN  01433334

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In the present study we have characterized eight human esophageal squamous carcinoma cell lines for levels of expression of cyclins D1, E, A and B1; CDKs 1, 2 and 4; the CDK inhibitors p16(INK4), p21(WAF1), and p27(KIP1); the retinoblastoma (Rb) protein; and in vitro CDK2- and CDK4-associated kinase activity; and also compared the growth properties of these cell lines. The level of the cyclin D1 protein varied by over 30-fold amongst the eight cell lines. The high level in two cell lines was associated with amplification of this gene, but in three cell lines it was due to post-transcriptional events. Amongst the eight cell lines there was a significant correlation between the levels of cyclin D1, Rb and p27(KIP1) proteins, and CDK4-associated kinase activity. Furthermore, when an exogenous cyclin D1 cDNA was over-expressed in the EC109 cell line by transfection, this led to increased expression of both Rb and p27(KIP1). There was, however, no correlation between the level of cyclin D1 expression and the cell doubling times, duration of the G1 phase, or colony-forming efficiency in agar. Two of the cell lines displayed a high level of the cyclin E protein, low levels of cyclin D1, lacked expression of the Rb protein and expressed high levels of the p16(INK4) protein. One of these cell lines displayed amplification of the latter gene. There was no correlation between the levels of cyclins E or A and in vitro CDK2 kinase activity, but CDK2 kinase activity was inversely correlated with the duration of the G1 phase of the cell cycle. Taken together, these studies indicate marked heterogeneity in the expression of cell cycle-related proteins amongst a series of esophageal carcinoma cell lines. The correlation between the levels of the cyclin D1, Rb and p27(Kip1) proteins suggest the existence of a homeostatic feedback loop between positive and negative acting components of the cell cycle machinery.

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チロシンキナーゼ阻害剤のアポトーシス誘導機構

井本正哉、清水史郎、梅沢一夫

日本農芸化学会誌、  ( 71 )  1997.05

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チロシンキナーゼ阻害剤アーブスタチンのアポトーシス誘導機構について概説した。(4ページ)

Pholipeptin, a novel cyclic lipoundecapeptide from Pseudomonas fluorescens.

宇井英明、三宅俊昭、飯沼寛信、井本正哉、長縄博、服部聖子、浜田雅、竹内富雄、梅沢純夫、梅沢一夫

J. Org. Chem. (Journal of Organic Chemistry)  62 ( 62 ) 103 - 108 1997.01

Research paper (scientific journal), Joint Work,  ISSN  00223263

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新規ホスホリパーゼＣ阻害剤フォリペプチンの構造決定について報告した。(6ページ)

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Induction of apoptotic cell death by tyrosine kinase inhibitor

Imoto M., Simizu S., Umezawa K.

Nippon Nogeikagaku Kaishi (Nippon Nogeikagaku Kaishi)  71 ( 5 ) 523 - 526 1997

Research paper (scientific journal), Accepted,  ISSN  00021407

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Inhibition of G1 cyclin expression in normal rat kidney cells by inostamycin, a phosphatidylinositol synthesis inhibitor.

出口敦子、井本正哉、梅沢一夫

J. Biochem. (Journal of Biochemistry)  120 ( 120 ) 1118 - 1122 1996.12

Research paper (scientific journal), Joint Work,  ISSN  0021924X

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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、G1サイクリンの発現を阻害することによりNRK細胞のG1期進行を阻害することを報告した。(5ページ)

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Synthesis of ribofuranosyl glycosides of echiguanines A and B, inhibitors of phosphatidylinositol 4-kinase

Sanpei K., Saito Y., Imoto M., Umezawa K., Kato K.

Bioorganic and Medicinal Chemistry Letters (Bioorganic and Medicinal Chemistry Letters)  6 ( 21 ) 2487 - 2490 1996.11

Research paper (scientific journal), Accepted,  ISSN  0960894X

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The synthesis of ribofuranosyl glycosides of echiguanines A and B, PI 4-kinase inhibitors, was achieved from 2-amino-4-chloropyrrolo[2,3-d]pyrimidine and 2,3-O-isopropylidene-5-O-(t-butyl) dimethylsilyl-α-D-ribofuranosyl chloride. The ribofuranosyl echiguanine A weakly inhibited PI 4-kinase.

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Involvement of hydrogen peroxide production in erbstatin-induced apoptosis in human small cell lung carcinoma cells

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

Cancer Research (Cancer Research)  56 ( 21 ) 4978 - 4982 1996.11

Research paper (scientific journal), Accepted,  ISSN  00085472

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Tyrosine kinase inhibitor, erbstatin, induced morphological apoptosis and DNA fragmentation in human small cell lung carcinoma (SCLC) cells. Erbstatin-induced apoptosis was inhibited by antioxidants, whereas erb- statin-inhibited tyrosine phosphorylation was not affected by them. Erbstatin was shown by means of flow cytometry to induce hydrogen peroxide generation. Furthermore, hydrogen peroxide induced morphological apoptosis and DNA fragmentation in the SCLC cells. We also demonstrated that erbstatin-induced hydrogen peroxide production and DNA fragmentation were partially suppressed by inhibition of protein synthesis. Thus, erbstatin-induced apoptosis would be due to hydrogen peroxide generation via newly synthesized protein.

Involvement of hydrogen peroxide production in erbstatin-induced apoptosis in human small lung carcinoma cells.

清水史郎、井本正哉、益田典幸、高田実、梅沢一夫

Cancer Res.  ( 56 )  1996.11

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チロシンキナーゼ阻害剤アーブスタチンが、小細胞肺癌細胞にアポトーシスを誘導するが、その過程で過酸化水素の生成が重要な役割を果たしていることを報告した。(5ページ)

Synthesis of ribopfuranosyl glycosides of echiguanines A and B, inhibitors of phosphatidy inositol 4-kinase.

三瓶香澄、斉藤義雄、井本正哉、梅沢一夫、加藤国木

Bioorg. & Med. Chem. Lett.  ( 6 )  1996

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ホスファチジルイノシトール4キナーゼ阻害剤エチグアニンAおよびBのグルコシル体を合成し報告した。(4ページ)

細胞情報伝達系に作用する物質の発見と細胞応答の解析

井本正哉

日本農芸化学会誌、  ( 69 )  1995.10

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我々の見いだした細胞情報伝達系の阻害剤の単離とそれらを用いた細胞応答の解析の結果を概説した。(7ページ)

Inhibition of phosphatidylinositol-specific phospholipase C activity by fluvirucin B2.

宇井英明、井本正哉、梅沢一夫

J. Antibiot.,  ( 48 )  1995.05

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ホスホリパーゼＣの阻害剤としてフルビルシンB2を放線菌培養液より単離し、それについて報告した。(4ページ)

Induction of erythroid differentiation in leukemic K562 cells by an S-adenosylhomocysteine hydrolase inhibitor, aristeromycin

Mizutani Y., Masuoka S., Imoto M., Kawada M., Umezawa K.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  207 ( 1 ) 69 - 74 1995.02

Research paper (scientific journal), Accepted,  ISSN  0006291X

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We have isolated an unusual nucleoside, aristeromycin, from the culture filtrate of Actinomycetes as a compound that induces normal morphology in v-ablts-NIH3T3 cells. Aristeromycin also induced erythroid differentiation in abl-expressing human chronic myelogenous leukaemia K562 cells. It did not affect the amount of Abl or the Abl-associated tyrosine kinase activity in either v-ablts-NIH3T3 or K562 cells. As a potent inhibitor of S-adenosylhomocysteine hydrolase, aristeromycin inhibited methylation of phosphatidylethanolamine to form phosphatidylcholine in K562 cells. Among aristeromycin analogues, the activity to inhibit S-adenosylhomocysteine hydrolase was paralleled with the induction of erythroid differentiation. Thus, aristeromycin inhibits abl functions indirectly, possibly by inhibiting biological methylations. © 1995 Academic Press, Inc.

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In situ inhibition of protein-tyrosine phosphatase by dephostatin.

井本正哉、出口敦子、早川哲、梅沢一夫

Cell. Pharmacol.  ( 2 )  1995.02

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新規チロシンホスファターゼ阻害剤デフォスタチンを用いて、細胞応答におけるチロシンホスファターゼの関与を報告した。(5ページ)

Induction of erythroid differentiation in leukaemic K562 cells by an S-adenosylhomocysteine hydrolase inhibitor, aristeromycin.

水谷陽子、舛岡正二郎、井本正哉、川田学、梅沢一夫

Biochem. Biopys. Res. Commun.,  ( 207 )  1995.02

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S-アデノシルホモシステインヒドラーゼ阻害剤アリステロマイシンが、白血病細胞K562を赤芽球様に分化する活性を有することを報告した。(5ページ)