RNA結合蛋白質による寿命制御機構の解明

2013 Fiscal Year Annual Research Report

• Project/Area Number: 25670138
• Research Institution: The University of Tokyo
• Principal Investigator: 秋山 徹 東京大学, 分子細胞生物学研究所, 教授 (70150745)
• Project Period (FY): 2013-04-01 – 2014-03-31
• Keywords: 寿命 / 老化 / 脂肪組織 / 分化

Outline of Annual Research Achievements

RNA結合タンパク質Mex-3Bの欠損マウスが雄特異的に寿命延長していることを見出し、Mex-3Bによる寿命制御機構の解明を試みた。
１）Mex-3B欠損マウスの表現系の解析を行ったところ、Mex-3B欠損マウスは加齢に伴う肥満に抵抗性で、特に脂肪組織量の顕著な減少が確認された。Mex-3Bはマウス、ヒトの両方において、全身にユビキタスに発現していることが確認されたが、絶食再摂食刺激や肥満負荷によるMex-3Bの遺伝子発現量の変化は、特に脂肪組織において顕著に認められた。以上の結果から、Mex-3Bの代謝機能臓器を脂肪組織であると仮定し、さらなる解析を行った。
２）in vitroにおける脂肪細胞分化誘導実験を3T3-L1細胞、MEF（Mouse Embryonic Fibroblast）およびSVC（Stromal Vascular Cell）を用いて行い、その時のMex-3Bの遺伝子発現変動を検討した。その結果、全ての細胞種においてMex-3Bの遺伝子発現は分化依存的に減少することが明らかになった。
３）さらに、Mex-3Bを欠損させた状態で3T3-L1細胞やMEFを脂肪細胞分化誘導させたところ脂肪細胞分化の抑制が確認されたため、Mex-3B欠損マウスがやせ型の表現系を示す原因として、脂肪細胞分化の減少が示唆された。
４）カロリー制限を行ったマウスの脂肪組織では、Mex-3BのmRNA、タンパク質レベルでの発現抑制が認められたことから、Mex-3B欠損マウスがカロリー制限を模倣して寿命延長の表現型を呈していることが示唆された。

Research Products

• [Journal Article] The miR-363-GATA6-Lgr5 pathway is critical for colorectal (2014)
  • Author(s): Shinnosuke Tsuji, Yoshihiro Kawasaki, Shiori Furukawa, Kenzui Taniue, Tomoatsu Hayashi, Masumi Okuno, Masaya Hiyoshi, Joji Kitayama, Tetsu Akiyama
  • Journal Title: Nature Communications Volume: 5 Pages: オンラインのみ
  • DOI: 10.1038/ncomms4150
  • Peer Reviewed
• [Journal Article] PCDH10 is required for the tumorigenicity of glioblastoma cells (2014)
  • Author(s): Kanae Echizen, Mitsutoshi Nakada , Tomoatsu Hayashi, Hemragul Sabit, Takuya Furuta, Miyuki Nakai, Ryo Koyama-Nasu, Yukiko Nishimura, Kenzui Taniue, Yasuyuki Morishita, Shinji Hirano, Kenta Terai, Tomoki Todo, Yasushi Ino, Akitake Mukasa, Shunsaku Takayanagi, Ryohei Ohtani, Nobuhito Saito, Tetsu Akiyama
  • Journal Title: Biochem Biophys Res Commun Volume: 444 Pages: 13-18
  • DOI: 10.1016/j.bbrc.2013.12.138
  • Peer Reviewed
• [Journal Article] Riccardo Fodde, Takao Senda. Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia (2014)
  • Author(s): Takanori Onouchi, Katsunori Kobayashi, Kazuyoshi Sakai, Atsushi Shimomura, Ron Smits, Chiho Sumi-Ichinose, Masafumi Kurosumi Keizo Takao, Ryuji Nomura, Akiko Iizuka-Kogo, Hidenori Suzuki,Kazunao Kondo, Tetsu Akiyama Tsuyoshi Miyakawa Riccardo Fodde and Takao Senda
  • Journal Title: Molecular Brain Volume: 7 Pages: オンラインのみ
  • DOI: 10.1186/1756-6606-7-21
  • Peer Reviewed
• [Journal Article] The miR-1-NOTCH3-Asef Pathway Is Important for Colorectal Tumor Cell Migration (2013)
  • Author(s): Shiori Furukawa, Yoshihiro Kawasaki, Masaya Miyamoto, Masaya Hiyoshi,Joji Kitayama, Tetsu Akiyama
  • Journal Title: PLoS ONE Volume: 8 Pages: オンラインのみ
  • DOI: 10.1371/journal.pone.0080609
  • Peer Reviewed
• [Journal Article] The pleiotrophin-ALK axis is required for tumorigenicity of glioblastoma stem cells (2013)
  • Author(s): R Koyama-Nasu, R Haruta, Y Nasu-Nishimura, K Taniue, Y Katou, K Shirahige, T Todo, Y Ino, A Mukasa, N Saito, M Matsui, R Takahashi, A Hoshino-Okubo, H Sugano, E Manabe, K Funato and T Akiyam
  • Journal Title: Oncogene Volume: 33 Pages: 2236-2244
  • DOI: 10.1038/onc.2013.168
  • Peer Reviewed
• [Journal Article] Differences in the localization of the APC-Asef/Asef2 complex between APC wild-type and mutant cells (2013)
  • Author(s): Yoshihiro Kawasaki, Shiori Furukawa, Rina Sato, Tetsu Akiyama
  • Journal Title: Cancer Sci. Volume: 8 Pages: 1135-1138
  • DOI: 10.1111/cas.12180
  • Peer Reviewed
• [Journal Article] The critical role of cyclin D2 in cell cycle progression and tumorigenicity of glioblastoma stem cells (2013)
  • Author(s): R Koyama-Nasu, Y Nasu-Nishimura, T Todo, Y Ino, N Saito, H Aburatani, K Funato, K Echizen, H Sugano, R Haruta, M Matsui, R Takahashi, E Manabe, T Oda and T Akiyama
  • Journal Title: Oncogene Volume: 32 Pages: 3840-3845
  • DOI: 10.1038/onc.2012.399
  • Peer Reviewed
• [Journal Article] Crystal structure of the guanylate kinase domain from Discs large homolog 1 (DLG1/SAP97). (2013)
  • Author(s): Shinji Mori, Yuta Tezuka, Akihiko Arakawa, Noriko Handa, Mikako Shirouzu, Tetsu Akiyama, Shigeyuki Yokoyama,
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 435 Pages: 334-338
  • DOI: 10.1016/j.bbrc.2013.04.056
  • Peer Reviewed
• [Journal Article] Alendronate attenuates eosinophilic airway inflammation associated with suppression of Th2 cytokines, Th17 cytokines, and eotaxin-2 (2013)
  • Author(s): Oh Sasaki, Mitsuru Imamura, Yusuke Yamazumi, Hiroaki Harada, Taku Matsumoto, Katsuhide Okunishi, Kazuyuki Nakagome, Ryoichi Tanaka, Tetsu Akiyama, Kazuhiko Yamamoto and Makoto Dohi
  • Journal Title: J. Immunol. Volume: 191 Pages: 2879-2889
  • DOI: 10.4049/jimmunol.1300460
  • Peer Reviewed
• [Journal Article] Novel mouse model for Gardner syndrome generated by a large-scale N-ethyl-N-nitrosourea mutagenesis program. (2013)
  • Author(s): Hideaki Toki, Maki Inoue, Hiromi Motegi, Osamu Minowa, Hiroaki Kanda, Noriko Yamamoto, Ami Ikeda, Yuko Karashima, Junko Matsui, Hideki Kaneda, Ikuo Miura, Tomohiro Suzuki, Shigeharu Wakana, Hiroshi Masuya, Yoichi Gondo, Toshihiko Shiroishi, Tetsu Akiyama, Ryoji Yao, Tetsuo Noda
  • Journal Title: Cancer Sci. Volume: 104 Pages: 937-944
  • DOI: 10.1111/cas.12161
  • Peer Reviewed
• [Journal Article] Decreased apoptosis and persistence of the common nephric duct during the development of an aberrant vesicoureteral junction in dlg1 gene-targeted mice (2013)
  • Author(s): Akiko Iizuka-Kogo, Tetsu Akiyama, Takao Senda.
  • Journal Title: Anat Rec. Volume: 296 Pages: 1936-1942
  • DOI: 10.1002/ar.22814
  • Peer Reviewed
• [Presentation] ”Long non-coding RNA ASBEL required for tumorigenicity of colon cancer (2014)
  • Author(s): Kenzui Taniue, Tetsu Akiyama
  • Organizer: Long Noncoding RNAs: Marching toward Mechanism
  • Place of Presentation: Santa Fe, New Mexico, USA
  • Year and Date: 2014-02-27 – 2014-03-04
• [Presentation] ASBEL, an ANA/BTG3 antisense transcript required for tumorigenicity of ovarian carcinoma. (2013)
  • Author(s): 谷上 賢瑞、秋山 徹
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2013-10-03 – 2013-10-05
• [Presentation] RNA結合タンパク質D8はc-junの転写後制御を介してAPC (Min/+)マウスにおける腫瘍形成を制御する (2013)
  • Author(s): 山角 祐介、渡邊 紘介、小田 健昭、佐藤 裕美、秋山 徹
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2013-10-03 – 2013-10-05
• [Presentation] 神経膠芽腫の発症における5-hydroxymethylcytosineの役割 / Role of 5-hydroxymethylcytosine in the tumorigenicity of glioblastoma cells (2013)
  • Author(s): 高井 弘基、秋山 徹
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2013-10-03 – 2013-10-05
• [Presentation] The role of miR-363-GATA6-Lgr5 pathway in colorectal tumorigenesis (2013)
  • Author(s): 川崎 善博、辻 真之介、古川 史織、谷上 賢瑞、林 寛敦、日吉 雅也 、北山 丈二 、秋山 徹
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2013-10-03 – 2013-10-05
• [Presentation] Functional analysis of a novel long ncRNA involved in the tumorigenicity of colorectal cancer. (2013)
  • Author(s): Kenzui Taniue,Akiko Kurimoto,Hironobu Sugimasa, Emiko Nasu, Takeshi Nagashima,Mariko Okada-Hatakeyama,Tetsu Akiyama
  • Organizer: AACR
  • Place of Presentation: ワシントンDC
  • Year and Date: 2013-04-06 – 2013-04-10
• [Patent(Industrial Property Rights)] 延寿命制御活性を有する物質をスクリーニングする方法 (2013)
  • Inventor(s): 秋山徹 他3名
  • Industrial Property Rights Holder: 秋山徹 他3名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-153564
  • Filing Date: 2013-07-24