Study of Ret proapoptotic activity and its relation with human diseases

2011 Fiscal Year Final Research Report

• Project/Area Number: 21590436
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya University
• Principal Investigator: ASAI Naoya 名古屋大学, 大学院・医学系研究科, 准教授 (80273233)
• Project Period (FY): 2009 – 2011
• Keywords: Retチロシンキナーゼ / 依存性受容体 / アポトーシス / 遺伝子改変マウス / 神経発生 / 下垂体発生 / 転写因子

Research Abstract

Ret tyrosine kinasse is a member of“dependence receptor"which induces apoptosis in the absence of its ligands. Ret is cleaved at D707 and D1017 by caspase, and intracellular fragment between D707 and D1017 can induce cell death. To determine the importance of Ret proapoptotic activity in vivo, we generated Ret D707N mutant mice. D707N Homozygote showed hyperplasia of neural cells in enteric, sympathetic and parapympathetic neural systems. In addition, adenopituitary lobe in pituitary gland was hyperplastic in D707N mice. To study the molecular mechanism of Ret proapoptotic activity, we examined the biological function of Ret fragment. Interestingly, Ret fragment is localized in the cell nucleus, and Ret fragment shows suppressive transcriptional activity.

Research Products

• [Journal Article] Partial impairment of c-Ret at tyrosine1062 accelerates age-related hearing loss in mice (2012)
  • Author(s): Ohgami N, Ida-Eto M, Sakashita N, Sone M, Nakashima T, Tabuchi K, Hoshino T, Shimada A, Tsuzuki T, Yamamoto M, Sobue G, Jijiwa M, Asai N, Hara A, Takahashi M, Kato M.
  • Journal Title: Neurobiol Aging Volume: 33(3) Pages: e25-34
  • Peer Reviewed
• [Journal Article] Loss of Sprouty2 partially rescues renalhy poplasia and stomach hypoganglionosisbut not intestinal aganglionosis in RetY1062F mutant mice (2011)
  • Author(s): Miyamoto R, Jijiwa M, Asai M, Kawai K, Ishida-Takagishi M, Mii S, Asai N, Enomoto A, Murakumo Y, Yoshimura A, Takahashi M.
  • Journal Title: Dev Biol Volume: 349(2) Pages: 160-8
  • Peer Reviewed
• [Journal Article] c-Ret-mediated hearing loss in mice with Hirschsprung disease (2010)
  • Author(s): Ohgami N, Ida-Eto M, Shimotake T, Sakashita N, Sone M, Nakashima T, TabuchiK, Hoshino T, Shimada A, Tsuzuki T, Yamamoto M, Sobue G, Jijiwa M, Asai N, Hara A, Takahashi M, Kato M.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 107(29) Pages: 13051-6
  • Peer Reviewed
• [Journal Article] Analysis of DOK-6 function in downstream signaling of RET in human neuroblastoma cells (2010)
  • Author(s): Kurotsuchi A, Murakumo Y, Jijiwa M, Kurokawa K, Itoh Y, Kodama Y, Kato T, Enomoto A, Asai N, Terasaki H, Takahashi M.
  • Journal Title: Cancer Sci Volume: 101(5) Pages: 1147-55
  • Peer Reviewed
• [Journal Article] Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis (2009)
  • Author(s): Lu BC, Cebrian C, Chi X, Kuure S, Kuo R, Bates CM, Arber S, Hassell J, MacNeil L, Hoshi M, Jain S, Asai N, Takahashi M, Schmidt-Ott KM, Barasch J, D' Agati V, Costantini F.
  • Journal Title: Nat Genet Volume: 41(12) Pages: 1295-302
  • Peer Reviewed
• [Journal Article] Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis (2009)
  • Author(s): Chi X, Michos O, Shakya R, Riccio P, Enomoto H, Licht JD, Asai N, Takahashi M, Ohgami N, Kato M, Mendelsohn C, Costantini F.
  • Journal Title: Dev Cell Volume: 17(2) Pages: 199-209
  • Peer Reviewed
• [Journal Article] RET遺伝子の機能と多発性内分泌腫瘍症2型 (2009)
  • Author(s): 浅井直也、高橋雅英
  • Journal Title: ホルモンと臨床 Volume: 57(3) Pages: 39-45
• [Presentation] 腸管神経におけるGDNF/Retシグナルの役割界 (2011)
  • Author(s): 浅井直也、時々輪真由美、高橋雅英
  • Organizer: 第88回日本生理学界・第116回日本解剖学会総会・全国学術集会
  • Year and Date: 20110300
• [Presentation] 依存性受容体としてのRETチロシンキナーゼの機能と腸管神経の発生 (2009)
  • Author(s): 高橋雅英、浅井直也
  • Organizer: 第62回日本自律神経学会総会
  • Place of Presentation: 和歌山県、和歌山市
  • Year and Date: 20091105-06
• [Presentation] Retチロシンキナーゼにより形成される細胞内断片の転写制御因子としての作用 (2009)
  • Author(s): 浅井直也、高橋雅英
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 神奈川県、横浜
  • Year and Date: 20091001-03
• [Presentation] Functional analysis of RET tyrosinekinase receptor as a dependence receptor (2009)
  • Author(s): Takahashi M, Asai N, Costantini F
  • Organizer: 2nd International symposium, Development of the enteric nervous system
  • Place of Presentation: London, UK
  • Year and Date: 20090222-25
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/patho2/