清水　史郎 (シミズ　シロウ)

Simizu, Siro

写真a

所属（所属キャンパス）

理工学部 応用化学科 （矢上）

職名

教授

HP

外部リンク
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総合紹介 【 表示 ／ 非表示 】

  • ケミカルバイオロジー、糖質科学、がん生物学を中心に研究を行っています。講義では化学の視点で生物学を理解できるように取り組んでいます。

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学歴 【 表示 ／ 非表示 】

  • 1993年03月

    慶應義塾大学, 理工学部, 応用化学科

    大学, 卒業

  • 1998年03月

    慶應義塾大学, 理工学研究科

    大学院, 修了, 博士

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学位 【 表示 ／ 非表示 】

  • 博士（工学）, 慶應義塾大学, 課程, 1998年03月

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研究分野 【 表示 ／ 非表示 】

  • ナノテク・材料 / 生体化学

  • ライフサイエンス / 分子生物学

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研究キーワード 【 表示 ／ 非表示 】

  • がん生物学

  • ケミカルバイオロジー

  • 糖質科学

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著書 【 表示 ／ 非表示 】

  • 実験医学

    宮崎 功、奥村 英夫、清水 史郎、長田 裕之, 2011年

    担当範囲: 79-83

  • 化学と工業

    叶 直樹、清水 史郎, 2011年

    担当範囲: 37-39

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論文 【 表示 ／ 非表示 】

  • Elucidation of structure-activity relationship of humulanolides and identification of humulanolide analog as a novel HSP90 inhibitor

    Saegusa J., Osada Y., Miura K., Sasazawa Y., Ogura A., Takao K.i., Simizu S.

    Bioorganic and Medicinal Chemistry Letters （Bioorganic and Medicinal Chemistry Letters)  60 2022年03月

    ISSN  0960894X

    　概要を見る

    Humulanolides are natural products isolated from Asteriscus, and the isolation and total synthesis of many types of humulanolides have been reported. In this study, we evaluated anti-proliferative activity of twelve humulanolides against various human cancer cell lines and found that humulanolide analog E, which was newly designed and synthesized, exhibited the highest anti-proliferative activity. Structure-activity relationship analysis revealed that α,β-unsaturated carbonyl moieties in humulanolides play an important role for anti-proliferative activity. To identify molecular targets of humulanolide analog E, we investigated various cell-based and in vitro assays. Treatment with humulanolide analog E against human fibrosarcoma HT1080 cells increased the expression level of HSP70 protein and decreased the levels of AKT and CDK4, which are HSP90 client proteins. Moreover, humulanolide analog E inhibited refolding of denatured luciferase protein via suppression of HSP90 activity in vitro. These results suggest that humulanolide analog E possesses the anti-proliferative activity against human cancer cells by inhibiting HSP90 functions.

  • ErbB4-mediated regulation of vasculogenic mimicry capability in breast cancer cells

    Kawahara R., Simizu S.

    Cancer Science （Cancer Science)  113 （ 3 ） 950 - 959 2022年03月

    ISSN  13479032

    　概要を見る

    ErbB4 is a member of the ErbB receptor tyrosine kinase family. It has both pro- and anti-oncogenic activities in tumors. Vasculogenic mimicry (VM), a phenomenon in which cancer cells form capillary-like structures without endothelial cells, has been recognized to be a cause of malignant phenotypes in some solid tumors. Here, we used an in vitro VM formation assay, and demonstrated that ErbB4 negatively regulated VM formation in human breast cancer cells. By using CRISPR/Cas9-mediated gene knockout, we verified that the depletion of endogenous ErbB4 improved the VM formation capability. Although treatment with neuregulin 1 (NRG1), a ligand of ErbB4, induced the phosphorylation of ErbB4 and promoted VM formation in a dose-dependent manner, it did not induce such activities in kinase-dead K751M ErbB4-overexpressing cells. Moreover, we examined the effect of the missense mutation E872K of ErbB4, which has been reported in multiple tumors, on VM formation, and found that the mutation enhanced the basal phosphorylation level and ErbB4-mediated VM formation in the absence of NRG1 stimulation. Whereas NRG1 stimulated VM formation, excessive activation of ErbB4 induced a negative effect. In E872K ErbB4-overexpressing cells, but not in wild-type ErbB4-overexpressing cells, the number of VM tubes was significantly decreased by low-dose treatment with the ErbB inhibitor afatinib. Taken together, our findings demonstrated the significance of ErbB4-mediated VM formation, and suggested the possibility of ErbB4 mutations as effective targets in breast cancer.

  • Scalable Syntheses and Biological Evaluation of Africane-Type Sesquiterpenoids

    Matsuda Y., Koyama T., Kawano S., Miura K., Simizu S., Saikawa Y., Nakata M.

    Chemistry and Biodiversity （Chemistry and Biodiversity)  19 （ 3 ）  2022年03月

    ISSN  16121872

    　概要を見る

    Practical total syntheses of africane-type sesquiterpenoids were realized by reexamination of a divergent strategy employing optimized three-component coupling followed by ring-closing metathesis and substrate-controlled cyclopropanation. This sequential eight-step conversion provided Δ9(15)-africanene, a common bicyclo[5.3.0]decane intermediate for the syntheses of africane derivatives, in more than twice the yield as in the previous approach. The scalability and robustness of this improved synthetic route were confirmed by gram-scale preparation of Δ9(15)-africanene. In vitro cell-based assays of the synthesized africane-type sesquiterpenoids disclosed that ester-incorporating derivatives showed cytotoxic activity against HeLa cells. The effect of relative and absolute configuration of africane-9,15-diol monoacetates on the cytotoxicity against HeLa cells was also investigated.

  • Methionine aminopeptidase-2 is a pivotal regulator of vasculogenic mimicry

    Shimizu S., Kawahara R., Simizu S.

    Oncology Reports （Oncology Reports)  47 （ 2 ）  2022年02月

    ISSN  1021335X

    　概要を見る

    Vasculogenic mimicry (VM) is the formation of a blood supply system that confers aggressive and metastatic properties to tumors and correlates with a poor prognosis in cancer patients. Thus, the inhibition of VM is considered an effective approach for cancer treatment, although such a mechanism remains poorly described. In the present study, we examined methionine aminopeptidase-2 (MetAP2), a key factor of angiogenesis, and demonstrated that it is pivotal for VM, using pharmacological and genetic approaches. Fumagillin and TNP-470, angiogenesis inhibitors that target MetAP2, significantly suppressed VM in various human cancer cell lines. We established MetAP2-knockout (KO) human fibrosarcoma HT1080 cells using the CRISPR/Cas9 system and found that VM was attenuated in these cells. Furthermore, re-expression of wild-type MetAP2 restored VM in the MetAP2-KO HT1080 cells, but the substitution of D251, a conserved amino acid in MetAP2, failed to rescue the VM. Collectively, our results demonstrate that MetAP2 is critical for VM in human cancer cells and suggest fumagillin and TNP-470 as potent VM-suppressing agents.

  • Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

    Mizuta H., Okada K., Araki M., Adachi J., Takemoto A., Kutkowska J., Maruyama K., Yanagitani N., Oh-hara T., Watanabe K., Tamai K., Friboulet L., Katayama K., Ma B., Sasakura Y., Sagae Y., Kukimoto-Niino M., Shirouzu M., Takagi S., Simizu S., Nishio M., Okuno Y., Fujita N., Katayama R.

    Nature Communications （Nature Communications)  12 （ 1 ）  2021年12月

    　概要を見る

    ALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

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総説・解説等 【 表示 ／ 非表示 】

  • Vasculogenic mimicry: A dynamic event of malignancy

    Simizu S.

    Biochimica et Biophysica Acta - General Subjects (Biochimica et Biophysica Acta - General Subjects)  1866 ( 3 )  2022年03月

    ISSN  03044165

  • C-Mannosylation: Previous studies and future research perspectives

    Niwa Y., Simizu S.

    Trends in Glycoscience and Glycotechnology (Trends in Glycoscience and Glycotechnology)  30 ( 177 ) E231 - E238 2018年11月

    ISSN  09157352

    　概要を見る

    © 2018 FCCA (Forum: Carbohydrates Coming of Age). C-linked glycosylation, one of the protein glycosylations, is a unique type of glycosylation in which an α-mannose is attached to the indole C2 carbon of a tryptophan residue via a C–C linkage and is so named C-mannosylation. C-mannosylation is enzymati-cally catalyzed in the endoplasmic reticulum (ER) lumen, and the N-terminal side Trp residue of the consensus amino acid sequence Trp-Xaa-Xaa-Trp/Cys (Xaa represents any amino acid) is often C-mannosylated. It has been reported that about 30 proteins are C-mannosylated, and the functions of C-mannosylation are becoming clear. In 2013, C. elegans dumpy-19 (dpy-19) was identified as a C-mannosyltransferase, and we revealed that DPY19L3, one of the human homologs of dpy-19, has similar activity in 2016. In this review, we describe previous studies about C-mannosylation, including our results and future research perspectives.

  • C-Mannosylation: Previous studies and future research perspectives

    Niwa Y., Simizu S.

    Trends in Glycoscience and Glycotechnology (Trends in Glycoscience and Glycotechnology)  30 ( 177 )  2018年11月

    ISSN  09157352

    　概要を見る

    © 2018 FCCA (Forum: Carbohydrates Coming of Age). C-linked glycosylation, one of the protein glycosylations, is a unique type of glycosylation in which an α-mannose is attached to the indole C2 carbon of a tryptophan residue via a C–C linkage and is so named C-mannosylation. C-mannosylation is enzymati-cally catalyzed in the endoplasmic reticulum (ER) lumen, and the N-terminal side Trp residue of the consensus amino acid sequence Trp-Xaa-Xaa-Trp/Cys (Xaa represents any amino acid) is often C-mannosylated. It has been reported that about 30 proteins are C-mannosylated, and the functions of C-mannosylation are becoming clear. In 2013, C. elegans dumpy-19 (dpy-19) was identified as a C-mannosyltransferase, and we revealed that DPY19L3, one of the human homologs of dpy-19, has similar activity in 2016. In this review, we describe previous studies about C-mannosylation, including our results and future research perspectives.

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研究発表 【 表示 ／ 非表示 】

  • R-spondin1 におけるリン酸化の機能解析

    西谷 拓海, 鈴木 健裕, 丹羽 祐貴, 三浦 一輝, 堂前 直, 清水 史郎

    日本農芸化学会関東支部会2018年度大会 (千葉) , 

    2018年10月
    , 

    ポスター発表

  • トポロジー解析によるDPY19L1のC-mannosyltransferase活性中心の探索

    横山 典弘, 柳原 凌太郎, 三浦 一輝, 丹羽 祐貴, 清水 史郎

    日本農芸化学会関東支部会2018年度大会 (千葉) , 

    2018年10月
    , 

    ポスター発表

  • ヒトC型糖転移酵素DPY19L3のプロモーター解析

    吉本 哲、三浦 一輝、清水 史郎

    日本農芸化学会関東支部会2018年度大会　 (千葉) , 

    2018年10月
    , 

    ポスター発表

  • Vibsanin A誘導体の生物活性評価および標的分子の同定

    三浦 一輝、松木 渉、高尾 賢一、清水 史郎

    日本農芸化学会関東支部会2018年度大会　 (千葉) , 

    2018年10月
    , 

    ポスター発表

  • C-mannosylation－基質と酵素の探索

    清水 史郎

    日本農芸化学会中部支部 第183回例会 (名古屋) , 

    2018年09月
    , 

    シンポジウム・ワークショップ パネル（指名）

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • 新たなC型糖修飾責任酵素の同定と基質タンパク質の解析

    2018年04月
    -
    2021年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 清水　史郎, 基盤研究(C), 補助金,  研究代表者

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受賞 【 表示 ／ 非表示 】

  • 日本がん転移学会　研究奨励賞

    清水 史郎, 2012年07月, 日本がん転移学会, ケミカルバイオロジーによる転移関連分子の理解と制御

    受賞区分： 国内学会・会議・シンポジウム等の賞

  • B.B.B.論文賞

    宮崎功、清水 史郎、一宮治美、川谷誠、長田裕之, 2009年03月, 日本農芸化学会, Robust and systematic drug screening method using chemical arrays and the protein library: identification of novel inhibitors of carbonic anhydrase II

    受賞区分： 国内学会・会議・シンポジウム等の賞

  • 日本癌学会奨励賞

    清水 史郎, 2004年10月, 日本癌学会, 薬剤耐性・転移に関与するがん分子標的の機能解析

    受賞区分： 国内学会・会議・シンポジウム等の賞

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担当授業科目 【 表示 ／ 非表示 】

  • 基礎理工学特別研究第１

    2023年度

  • 化学防災と安全工学

    2023年度

  • 細胞生物化学

    2023年度

  • 生物化学

    2023年度

  • 卒業研究

    2023年度

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所属学協会 【 表示 ／ 非表示 】

  • 日本糖質学会, 

    2015年
    -
    継続中

  • 日本がん分子標的治療学会, 

    2009年
    -
    継続中

  • 日本ケミカルバイオロジー学会, 

    2008年
    -
    継続中

  • 日本がん転移学会, 

    2006年
    -
    継続中

  • 日本癌学会, 

    1992年
    -
    継続中
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委員歴 【 表示 ／ 非表示 】

  • 2015年
    -
    継続中

    評議員, 日本がん転移学会

  • 2009年
    -
    継続中

    評議員, 日本がん分子標的治療学会

  • 2008年
    -
    継続中

    会員, 日本ケミカルバイオロジー学会

  • 1992年
    -
    継続中

    会員, 日本癌学会

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