Targeting Mnk/eIF4E pathway for cancer therapy

• Project/Area Number: 23590364
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Hiroshima University
• Principal Investigator: UEDA Takeshi 広島大学, 原爆放射線医科学研究所, 助教 (60585149)
• Co-Investigator(Kenkyū-buntansha): HONDA Hiroaki 広島大学, 原爆放射線医科学研究所, 教授 (40245064) ; FUKUNAGA Rikiro 大阪薬科大学, 薬学部, 教授 (40189965)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: シグナル伝達 / 翻訳制御

Research Abstract

MAP kinase-interacting kinase 1 (Mnk1) and Mnk2 are protein-serine/threonine kinases that are activated by ERK or p38 and phosphorylate a translation initiation factor eIF4E. We have previously reported that Mnk1/2 double deficiency delays tumor development in a mouse lymphoma model and that suppression of Mnk1 significantly reduces the tumorigenic activity of xenografted human glioma cells. To further investigate the regulatory network of Mnks, we attempted to search for Mnk1- interacting proteins. The Flag-tagged wild-type Mnk1 and kinase-dead Mnk1 complexes were affinity-purified from mouse embryonic fibroblasts, and then the identities of binding proteins were determined by tandem mass spectrometry. As a result, a 130kDa deubiquitinase was identified as a novel Mnk1-binding partner. We are currently exploring the impact of the interaction between these proteins.

Research Products

• [Journal Article] Interplay between chromatin-modifying enzymes controls colon cancer progression through Wnt signaling (2014)
  • Author(s): Chevillard-Briet M, Quaranta M, Grézy A, Mattera L, Courilleau C, Philippe M, Mercier P, Corpet D, Lough J, Ueda T, Fukunaga R, Trouche D, Escaffit F
  • Journal Title: Hum Mol Genet Volume: 23(8) Pages: 2120-2131
  • Peer Reviewed
• [Journal Article] Acquired deficiency of a20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function (2014)
  • Author(s): Nagamachi A, Nakata Y, Ueda T, Yamasaki N, Ebihara Y, Tsuji K, Honda Z, Takubo K, Suda T, Oda H, Inaba T, Honda H
  • Journal Title: PLoS On Volume: 9(1)
  • Peer Reviewed
• [Journal Article] Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model (2013)
  • Author(s): Berger T, Ueda T, Arpaia E, Chio II, Shirdel EA, Jurisica I, Hamada K, You-Ten A, Haight J, Wakeham A, Cheung CC, Mak TW
  • Journal Title: Oncogene Volume: 32(41) Pages: 4989-4994
  • Peer Reviewed
• [Journal Article] Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15 (2013)
  • Author(s): Inoue S, Hao Z, Elia AJ, Cescon D, Zhou L, Silvester J, Snow B, Harris IS, Sasaki M, Li WY, Itsumi M, Yamamoto K, Ueda T, Dominguez-Brauer C, Gorrini C, Chio II, Haight J, You-Ten A, McCracken S, Wakeham A, Ghazarian D, Penn LJ, Melino G, Mak TW
  • Journal Title: Genes Dev Volume: 27(10) Pages: 1101-11114
  • Peer Reviewed
• [Journal Article] CIZ1, a p21 (Cip1/Waf1) -interacting protein, functions as a tumor suppressor in vivo (2013)
  • Author(s): Nishibe R, Watanabe W, Ueda T, Yamasaki N, Koller R, Wolff L, Honda Z, Ohtsubo M, Honda H
  • Journal Title: FEBS Lett Volume: 587(10) Pages: 1529-1535
  • Peer Reviewed
• [Journal Article] MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells (2013)
  • Author(s): Gorentla BK, Krishna S., Shin J., Inoue M., Shinohara ML, Grayson JM, Fukunaga R, Zhong XP
  • Journal Title: J Immunol Volume: 190(3) Pages: 1026-1037
  • Peer Reviewed
• [Journal Article] MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells (2013)
  • Author(s): Shi Y, Frost P, Hoang B, Yang Y, Fukunaga R, Gera J, Lichtenstein A
  • Journal Title: Oncogene Volume: 32(2) Pages: 190-197
  • Peer Reviewed
• [Journal Article] Sprouty proteins are negative regulators of interferon (IFN)-signaling and IFN-inducible biological responses (2012)
  • Author(s): Sharma B, Joshi S, Sassano A, Majchrzak B, Kaur S, Aggarwal P, Nabet B, Bulic M, Stein BL, McMahon B, Baker DP, Fukunaga R, Altman JK, Licht JD, Fish EN, Platanias LC
  • Journal Title: J Biol Chem Volume: 287(50) Pages: 42352-42360
  • Peer Reviewed
• [Journal Article] EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms (2012)
  • Author(s): Ueda T, Sanada M, Matsui H, Yamasaki N, Honda ZI, Shih LY, Mori H, Inaba T, Ogawa S, Honda H
  • Journal Title: Leukemia Volume: 26(12) Pages: 2557-2560
  • Peer Reviewed
• [Journal Article] D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function (2012)
  • Author(s): Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, Chio II, Cairns RA, McCracken S, Wakeham A, Haight J, Ten AY, Snow B, Ueda T, Inoue S, Yamamoto K, Ko M, Rao A, Yen KE, Su SM, Mak TW
  • Journal Title: Genes Dev Volume: 26(18) Pages: 2038-2049
  • Peer Reviewed
• [Journal Article] TRADD contributes to tumour suppression by regulating ULF-dependent p19(Arf) ubiquitylation (2012)
  • Author(s): Chio II, Sasaki M, Ghazarian D, Moreno J, Done S, Ueda T, Inoue S, Chang YL, Chen NJ, Mak TW
  • Journal Title: Nat Cell Biol Volume: 14(6) Pages: 625-633
  • Peer Reviewed
• [Journal Article] Essential role for Mnk kinases in type II interferon (IFN{gamma}) signaling and its suppressive effects on normal hematopoiesis (2011)
  • Author(s): Joshi S, Sharma B, Kaur S, Majchrzak B, Ueda T, Fukunaga R, Verma AK, Fish EN, Platanias LC
  • Journal Title: J Biol Chem Volume: 286(8) Pages: 6017-6026
  • Peer Reviewed
• [Presentation] 遺伝子改変マウスを用いた造血器腫瘍関連EED Ile363Met変異体の解析 (2013)
  • Author(s): 上田健, 真田昌, 松井啓隆, 山崎憲政, 本田善一郎, 森啓, LEE-YUNG SHIH, 稲葉俊哉, 小川誠司, 本田浩章
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-12
• [Presentation] Identification of interacting partners for MAP kinase-interacting kinase 1 (2013)
  • Author(s): 上田健, 福永理己郎, Roumiana Alexandrova, Theo Goh, Tak W. Mak, 本田浩章
  • Organizer: 第86回日本生化学会
  • Place of Presentation: 横浜
  • Year and Date: 2013-09-11
• [Presentation] MDSで同定されたポリコーム複合体PRC2構成因子EEDの機能欠失型変異体の解析 (2012)
  • Author(s): 上田健, 真田昌, 松井啓隆, 山崎憲政, 本田善一郎, 森啓, LEE-YUNG SHIH, 稲葉俊哉, 小川誠司, 本田浩章
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-19
• [Presentation] 骨髄異形成症候群におけるポリコーム複合体PRC2構成因子EEDの機能欠失型変異 (2011)
  • Author(s): 上田健, 真田昌, 松井啓隆, 山崎憲政, 本田善一郎, 森啓, LEE-YUNG SHIH, 稲葉俊哉, 小川誠司, 本田浩章
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] 癌の治療標的としてのMnk/eIF4E経路 (2011)
  • Author(s): 上田健
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-22
• [Presentation] 癌の治療標的としてのMnk/eIF4E経路 (2011)
  • Author(s): 上田 健
  • Organizer: 日本生化学会(招待講演)
  • Place of Presentation: 京都
• [Presentation] Identification of interacting partners for MAP kinase-interacting kinase 1
  • Author(s): 上田 健、福永理己郎、Roumiana Alexandrova、Theo Goh、Tak W. Mak、本田浩章
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜