クロライドイオンによるAkt/JNKの活性化を介した細胞生存・死の決定機構

2007 Fiscal Year Annual Research Report

• Project/Area Number: 19590212
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: 新里 直美 Kyoto Prefectural University of Medicine, 医学研究科, 准教授 (00237645)
• Co-Investigator(Kenkyū-buntansha): 丸中 良典 京都府立医科大学, 医学研究科, 教授 (00127036) ; 宮崎 裕明 京都府立医科大学, 医学研究科, 助教 (30360027) ; 中島 謙一 京都府立医科大学, 医学研究科, 助教 (40398392) ; 徳田 深作 京都府立医科大学, 医学研究科, 助教 (00433277)
• Keywords: Akt / JNK / チロシンリン酸化 / クロライドイオン / 細胞死 / NKCC

Research Abstract

我々は、クロライドイオンが細胞生存の重要な制御因子であるAktおよびJNKの活性制御を介して細胞の運命(生死)を決定している可能性があると考えた。一方、細胞内のクロライドイオン濃度は、クロライド分泌を担うイオン輸送体転写・活性制御により調節され、NKCCやC1-channelがチロシンリン酸化依存的な制御を受けることも明らかにしており、増殖因子などによる制御の可能性も示唆されている。そこで、「細胞内クロライドイオン濃度を制御するNKCCの転写・活性制御によるAktおよびJNKの活性制御を介し細胞の生死が決定される」という研究仮説に基づいて研究を行った。
そこで、平成19年度において次のことを明らかにした。
(1)培養細胞(腎尿細管由来上皮細胞A6細胞)において、人為的に細胞内のクロライド濃度を様々に変化させると、細胞の生死の制御に関わるシグナル分子であるAktおよびJNKのチロシンリン酸化レベルが、クロライド濃度依存的に増大することを明らかにした。
(2)Aktのチロシンリン酸化増大のメカニズムは、src kinaseの活性化に見られたようなチロシン脱リン酸か酵素の不活性化によるものではなく、上流のチロシンリン酸か酵素の活性化に依存することを明らかにした。

Research Products

• [Journal Article] Regulation of the paracellular Na+ and Cl- conductances by the NaCl-generated osmotic gradient in a manner dependent on the direction of osmotic gradients. (2008)
  • Author(s): Tokuda S, Niisato N, Nakajima K, Marunaka Y.
  • Journal Title: Biochem Biophys Res Commun. 366(2) Pages: 464-70
  • Peer Reviewed
• [Journal Article] Chloride ions control the Gl/S cell-cycle checkpoint by regulating the expression of p21 through a p53-independent pathway in human gastric cancer cells. (2008)
  • Author(s): Miyazaki H, Shiozaki A, Niisato N, Ohsawa R, Itoi H, Ueda Y, Otsuji E, Yamagishi H, Iwasaki Y, Nakano T, Nakahari T, Marunaka Y.
  • Journal Title: Biochem Biophys Res Commun. 366(2) Pages: 506-12
  • Peer Reviewed
• [Journal Article] Intracellular calcium plays a role as the second messenger of hypotonic stress in gene regulation of SGK1 and ENaC in renal epithelial A6 cells. (2008)
  • Author(s): Taruno A, Niisato N, Marunaka Y.
  • Journal Title: Am J Physiol Renal Physiol. 294(1) Pages: F177-86
  • Peer Reviewed
• [Journal Article] Regulation of paracellular ion conductances by NaCl gradients in renal epithelial cells. (2007)
  • Author(s): Tokuda S, Niisato N, Marunaka Y.
  • Journal Title: Biochem Biophys Res Commun. 363(3) Pages: 566-571
  • Peer Reviewed
• [Journal Article] Epithelial Na+ channel and ion transport in human nasal polyp and paranasal sinus mucosa. (2007)
  • Author(s): Yasuda M, Niisato N, Miyazaki H, Iwasaki Y, Hama T, Dejima K, Hisa Y, Marunaka Y.
  • Journal Title: Biochem Biophys Res Commun. 362(3) Pages: 753-758
  • Peer Reviewed
• [Journal Article] Chloride-dependent acceleration of cell cycle via modulation of Rb and cdc2 in osteoblastic cells. (2007)
  • Author(s): Maki M, Miyazaki H, Nakajima K, Yamane J, Niisato N, Morihara T, Kubo T, Marunaka Y.
  • Journal Title: Biochem Biophys Res Commun. 361(4) Pages: 1038-1043
  • Peer Reviewed
• [Journal Article] Aldosterone-induced modification of osmoregulated ENaC trafficking. (2007)
  • Author(s): Niisato N, Taruno A, Marunaka Y.
  • Journal Title: Biochem Biophys Res Commun. 361(1) Pages: 162-168
  • Peer Reviewed
• [Journal Article] HCO_3^--dependent pH_i recovery and overacidification induced by NH_4^+ pulse in rat lung alveolar type II cells: HCO_3^--dependent NH_3 excretion from lungs? (2007)
  • Author(s): Tokuda S, Shimamoto C, Yoshida H, Murao H, Kishima G, Ito S, Kubota T, Hanafusa T, Sugimoto T, Niisato N, Marunaka Y, Nakahari T.
  • Journal Title: Pflugers Arch. 455(2) Pages: 223-239
  • Peer Reviewed
• [Journal Article] Essential role of NKCC1 in NGF-induced neurite outgrowth. (2007)
  • Author(s): Nakajima K, Miyazaki H, Niisato N, Marunaka Y.
  • Journal Title: Biochem Biophys Res Commun. 359(3) Pages: 604-610
  • Peer Reviewed
• [Journal Article] Involvement of p38 MAPK in hypotonic stress-induced stimulation of beta-and gamma-ENaC expression in renal epithelium. (2007)
  • Author(s): Niisato N, Taruno A, Marunaka Y.
  • Journal Title: Biochem Biophys Res Commun. 358(3) Pages: 819-824
  • Peer Reviewed
• [Journal Article] Abnormal expression of ENaC and SGK1 mRNA induced by dietary sodium in Dahl salt-sensitively hypertensive rats. (2007)
  • Author(s): Aoi W, Niisato N, Sawabe Y, Miyazaki H, Tokuda S, Nishio K, Yoshikawa T, Marunaka Y.
  • Journal Title: Cell Biol Int. 31(10) Pages: 1288-1291
  • Peer Reviewed
• [Journal Article] Action of neltenexine on anion secretion in human airway epithelia. (2007)
  • Author(s): Niisato N, Hasegawa I, Tokuda S, Taruno A, Nakajima K, Miyazaki H, Iwasaki Y, Marunaka Y.
  • Journal Title: Biochem Biophys Res Commun 356(4) Pages: 1050-1055
  • Peer Reviewed
• [Journal Article] Hypotonicity stimulates renal epithelial sodium transport by activating JNK via receptor tyrosine kinases. (2007)
  • Author(s): Taruno A, Niisato N, Marunaka Y.
  • Journal Title: Am J Physiol Renal Physiol. 293(1) Pages: F128-F138
  • Peer Reviewed
• [Journal Article] Physiological significance of hypotonicity-induced regulatory volume decrease: reduction in intracellular Cl-concentration acting as an intracellular signaling. (2007)
  • Author(s): Miyazaki H, Shiozaki A, Niisato N, Marunaka Y.
  • Journal Title: Am J Physiol Renal Physiol. 292(5) Pages: F1411-F1417
  • Peer Reviewed
• [Presentation] Intracellular chloride-dependent modulation of aldosterone action on Na^+ reabsorprion. (2007)
  • Author(s): Niisato N, Marunaka Y.
  • Organizer: Aldosterone and ENaC: from Gene to Disease
  • Place of Presentation: Zermatt, Switzerland
  • Year and Date: 20071003-07
• [Presentation] Regulation of ENaC function by hypotonic stress in renal epithelial A6 cells: genomic and non-genomic mechanisms. (2007)
  • Author(s): Taruno A, Niisato N, Marunaka Y.
  • Organizer: Aldosterone and ENaC: from Gene to Disease
  • Place of Presentation: Switzerland
  • Year and Date: 20071003-07