がん細胞の分化・極性の異常と細胞極性シグナリング

2008 Fiscal Year Annual Research Report

• Project/Area Number: 17014076
• Research Institution: Yokohama City University
• Principal Investigator: 大野 茂男 Yokohama City University, 医学研究科, 教授 (10142027)
• Co-Investigator(Kenkyū-buntansha): 鈴木 厚 横浜市立大学, 医学研究科, 准教授 (00264606) ; 秋本 和憲 横浜市立大学, 医学部, 助教 (70285104) ; 廣瀬 智威 横浜市立大学, 医学部, 助教 (20381668)
• Keywords: aPKC / ASIP / PAR-3 / PAR-6 / 線虫

Research Abstract

組織構築の基本原理の一端とヒトがん組織における細胞の分化・極性の異常の具体的な様相を明らかとする事を目的として、がんの悪性度の重要な指標である細胞の極性の制御の仕組みについて、細胞極性タンパク質と他のシグナル系との関わりに特に注目して分子・細胞レベル・マウス個体レベルで解析・検証した。さらに、ヒトがんにおける細胞極性タンパク質の異常を解析した。下記の成果を得た。
具体的には、細胞極性タンパク質aPKCが、PtdIns(3, 4, 5)P3をapical膜から排除してバソラテラル膜に濃縮させる作用があることを見いだした。細胞接着装置AJの形成のリアルタイムイメージングにより、細胞極性タンパク質aPKCが上皮細胞のアピカル側を取り囲むアクチン繊維の内側への引力と拮抗して細胞接着装置の熟成に関わる事を見いだした。PAR-3とaPKC-PAR-6からなる複合体が、アピカル膜ドメインの形成過程に必須であることを見いだした。細胞極性タンパク質PAR-1が細胞外ラミニンの組織化の役割を担うことを発見した。さらに、その機構の解析から、PAR-1がラミニンとして知られていたユートロフィン・ジストログリカン複合体と直接相互作用する事により、細胞外ラミニンの組織化に関わる事を見いだした。細胞内の極性タンパク質が、細胞外の基質の制御に関わる新たな概念を提示できた。細胞極性と細胞死のシグナル経路を結ぶ新規分子を見いだした。aPKCの乳腺上皮細胞におけるノックアウトマウスの解析から、aPKCが性成熟後の乳腺上皮細胞の増殖制御と組織化に必須であることを見いだした。さらに、ヒト乳癌において高頻度にaPKCの異常発現が起きており、それが病理型と相関していることを見いだした。

Research Products

• [Journal Article] Intracellular polarity protein PAR-1 regulates extracellular laminin assembly by regulating the dystroglycan Complex (2009)
  • Author(s): Masuda-Hirata M, Suzuki A, Amano Y, Yamashita K, Ide M, Yamanaka T, Sakai M, Imamura Mand Ohno S
  • Journal Title: Genes to Cells (in press)
  • Peer Reviewed
• [Journal Article] SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay (2009)
  • Author(s): Yamashita A, Izumi N, Kashima I, Ohnishi T, Saari B, Katsuhata Y, Muramatsu R, Morita T, Iwamatsu A, Hachiya T, Kurata R, Hirano H, Anderson P, Ohno S
  • Journal Title: Genes & Development 23(9) Pages: 1091-1105
  • Peer Reviewed
• [Journal Article] Interaction between PAR-3 and the aPKC-PAR-6 complex is indispensable for apical domain development of epithelial cells (2009)
  • Author(s): Horikoshi Y, Suzuki A, Yamanaka T, Sasaki K, Mizuno K, Sawada H, Yonemura S, Ohno S
  • Journal Title: Journal of Cell Science 122(10) Pages: 1595-1606
  • Peer Reviewed
• [Journal Article] An essential role of the universal polarity protein, aPKClambda, on the maintenance of podocyte slit diaphragms (2009)
  • Author(s): Hirose T, Satoh D, KuriharaH, Kusaka C, Hirose H, Akimoto K, Matsusaka T, Ichikawa I, Noda T, Ohno S
  • Journal Title: PLoS ONE 4(1) Pages: e4194
  • Peer Reviewed
• [Journal Article] aPKC enables development of zonula adherens by antagonizing centripeta 1 contraction of the circumferential actomyosin cables (2008)
  • Author(s): Kishikawa M, Suzuki A, Ohno S
  • Journal Title: Journal of Cell Science 121(Pt15) Pages: 2481-2492
  • Peer Reviewed
• [Journal Article] The overexpression and altered localization of the atypical protein kinase C lambda/iota in breast cancer correlates with the pathologic type of these tumors (2008)
  • Author(s): Kojima Y, Akimoto K, Nagashima Y, Ishiguro H, Shirai S, Chishima T, Ichikawa Y, Ichikawa T, Sasaki T, Kubota Y, InayamaY, Aoki I, Ohno S, Shimada H
  • Journal Title: Hum Pathol 39(6) Pages: 824-831
  • Peer Reviewed
• [Journal Article] aPKC restricts the basolateral determinant PtdIns(3,4,5)P3 to the basal region (2008)
  • Author(s): Takahama S, Hirose T, Ohno S
  • Journal Title: Biochem. Biophys. Res. Commun 368(2) Pages: 249-255
  • Peer Reviewed
• [Presentation] The cell polarity protein, aPKClambda, plays a critical rolein the maintenance of podocyte slit diaphragms, specific type if epithelial intercellular junctions (2008)
  • Author(s): Hirose T, Satoh D, Kurihara H, kusaka C, Hirose H, Akimoto K, Matsusaka T, Ichikawa I, Noda T, Ohno S
  • Organizer: BMB2008
  • Place of Presentation: Kobe
  • Year and Date: 20081209-10
• [Presentation] Conditionally Replicative Adenoviral Vectors for the Treatment of Gastric Cancer (2008)
  • Author(s): Kosaka T, Ono H, Kunisaki C, Julia D, Ohno S, Yamamoto M, Shimada H
  • Organizer: The 67th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Nagoya
  • Year and Date: 20081028-30
• [Presentation] The role of aPKC lambda in prostate cancer progression (2008)
  • Author(s): Ishiguro H, Akimoto K, Nagashima Y, Kojima Y, Ishiguro Y, Sasaki T, Umemura H, Ohno S, Kubota Y
  • Organizer: The 67th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Nagoya
  • Year and Date: 20081028-30
• [Presentation] Translation Termination Complex During Nonsense-Mediated MRNA Decay (2008)
  • Author(s): Yamashita A, Izumi N, Kashima I, Katsuhata Y, Muramatsu R, Ohno S
  • Organizer: 2008 Cold spring harver labatory meeting on translational control
  • Place of Presentation: New York, USA
  • Year and Date: 20080903-07
• [Presentation] aPKC1 regulates mammary-gland morphogenesis through the transcriptiona 1 suppression of ErbB2/HER-2 gene (2008)
  • Author(s): Akimoto K, Nagashima K, Ishiguro H, Kojima Y, Kim M, Sasaki K, Noda T, Ohno S
  • Organizer: Second JCA-AACR Special Joint Conference, The Latest Advances in Breast Cancer Research : From Basic Science to Therapeutics
  • Place of Presentation: Awaji, Hyogo, Japan
  • Year and Date: 20080714-16
• [Presentation] The formation of SMG-1 : Upfl : eRF1 : eRF3 complex (SURF) on ribosomes precedes translation-dependent-Upfl phosphorylation during nonsense-medi ated mRNA decay (2008)
  • Author(s): Yamashita A, Kashima I, Izumi N, Katsuhata Y, Muramatsu R, Ohno S
  • Organizer: THE 21st NAITO CONFERENCE"Nuclear Dynamics and RNA[I]"
  • Place of Presentation: Yamanashi, Japan
  • Year and Date: 20080624-27
• [Presentation] Possible involvement of PAR-3 in the regulation of slit diaphragm through the direct interaction with Nephrin (2008)
  • Author(s): Satoh D, Hirose T, Kurihara H, Ohno S
  • Organizer: The 7th International Podocyte Conference
  • Place of Presentation: Toronto, Canada
  • Year and Date: 20080604-06
• [Presentation] The cell polarity protein aPKCλ plays a critical role in the maintenance of podocyte slit diaphragms (2008)
  • Author(s): Hirose T, Satoh D, Kurihara H, Akimoto K, Matsusaka T, Ichikawa I, Noda, T, Ohno S
  • Organizer: The 7th International Podocyte Conference
  • Place of Presentation: Toronto, Canada
  • Year and Date: 20080604-06
• [Presentation] Conditional depletion of aPKCλ in eye lens causes microphthalmia and cataract (2008)
  • Author(s): Sugiyama Y, Akimoto K, Robinson M. L, Quinlan, R. A, Ohno S
  • Organizer: ARVO (Association for Research in Vision and Ophthalmology) 2008Annual Meeting, 2008
  • Place of Presentation: Florida USA
  • Year and Date: 20080427-0501
• [Remarks]
  • URL: http://www-user.yokohama-cu.acjp/?ohnos//Japanease/indexihtnal