DNAポリメラーゼイオタ欠損マウスの作製とその肺発がん感受性の解析

2008 Fiscal Year Annual Research Report

• Project/Area Number: 18590384
• Research Institution: Kochi University
• Principal Investigator: 李 康弘 Kochi University, 教育研究部医療学系, 教授 (10261405)
• Keywords: 肺発がん / 抵抗性遺伝子 / Polτ / ノックアウトマウス

Research Abstract

我々が発見したマウスの肺発がん抵抗性遺伝子座Par2(Pulmonary adenoma resistance2)は第18番染色体上に存在し、多遺伝子支配下にある遺伝的肺発がん感受性を修飾する主要な遺伝因子のとして働く。平成17年度までの逆行遺伝学的研究により、我々はPar2の有力な候補遺伝子としてPoltを同定することができた。PoltはDNA損傷乗越え能力を有するDNAポリメラーゼをコードしており、発がん物質等によって損傷を受けたDNAの複製や修復に関与しているものと考えられる。Polt々はマウスおよびヒトでアミノ酸変化を伴う著明な多型を示す。この多型よる機能変化が、体細胞遺伝子突然変異をその本質とする肺発がんの第一段階、即ちイニシエーションの効率に影響するものと推測される。しかし、Par2の責任遺伝子がPoltであることを直接証明するためには、Poltノックアウトマウスを作製し、その肺発がん感受性を調べねばならない。19年度前半までにノックアウトに必要なターゲティングベクターの設計ならび作製と、その胚幹細胞株への導入を行ったが、ノックアウトマウス創出に適する胚幹細胞クローンを得ることができなかった。その後新たなターゲティングベクターの設計と作製を行って実験を進めたところ、良好なノックアウト胚幹細胞クローンが得られ、今年度終盤になってようやくノックアウトマウスの樹立に成功した。ただし、研究途中でターゲティングベクターの再設計を要したことから、当初の計画に比して約1年間の遅れを生じた結果、ノックアトマウスの肺発がん感受性実験を20年度内に終了することができなかった。今後は新たな研究申請による外部資金獲得に努め、本研究の最終目的達成を目指したい。

Research Products

• [Journal Article] Ureteral small cell carcinoma. (2009)
  • Author(s): Kuroda N, Katto K, Tamura M, Shiotsu T, Inoue K, Ohara M, Mizuno K, Lee GH
  • Journal Title: Med Mol Morphol 42 Pages: 55-57
  • Peer Reviewed
• [Journal Article] The Kras2 oncogene and mouse lung carcinogenesis. (2008)
  • Author(s): Lee GH
  • Journal Title: Med Mol Morphol 41 Pages: 199-203
  • Peer Reviewed
• [Journal Article] Coexistent adenomyoepithelioma and invasive ductal carcinoma of the breast : presentation as separate tumors. (2008)
  • Author(s): Kuroda N, Fujishima N, Ohara M, Hirouchi T, Mizuno K, Hayashi Y, Lee GH
  • Journal Title: Med Mol Morphol 41 Pages: 238-242
  • Peer Reviewed
• [Journal Article] Chromophobe renal cell carcinoma : useful diagnostic application of imprint cytology and fluorescence in situ hybridization of chromosomes 10 and 21 in two cases of typical and eosinophilic variants. (2008)
  • Author(s): Kuroda N, Katto K, Yamaguchi T, Kawada T, Imamura Y, Hes O, Michal M, Shuin T, Lee GH
  • Journal Title: Med Mol Morphol 41 Pages: 227-232
  • Peer Reviewed
• [Journal Article] Ultrastructural study of the morphogenesis of human herpesvirus 6 type B in human T-lymphotropic virus type I-producing lymphoid cells. (2008)
  • Author(s): Ohtsuki Y, Daibata M, Bandobashi K, Lee GH, Furihata M, Yokoyama A, Miyoshi I
  • Journal Title: Med Mol Morphol 41 Pages: 204-210
  • Peer Reviewed
• [Journal Article] Expression of fascin-1, an actin-bundling protein, in migrating hepatoblasts during rat liver development. (2008)
  • Author(s): Hayashi Y, Toda K, Saibara T, Okamoto S, Osanai M, Enzan H, Lee GH
  • Journal Title: Cell Tissue Res 334 Pages: 219-226
  • Peer Reviewed
• [Journal Article] Mucinous tubular and spindle cell carcinoma with Fuhrman nuclear grade 3 : a histological, immunohistochemical, ultrastructural and FISH study. (2008)
  • Author(s): Kuroda N, Hes O, Michal M, Nemcova J, Gal V, Yamaguchi T, Kawada T, Imamura Y, Hayashi Y, Lee GH
  • Journal Title: Histol Histopathol 23 Pages: 1517-1523
  • Peer Reviewed
• [Journal Article] Elastofibroma : a histochemical, immunohistochemical, and ultrastructural study of two patients. (2008)
  • Author(s): Kuroda N, Hamaguchi N, Ohara M, Hirouchi T, Mizuno K, Hayashi Y, Lee GH
  • Journal Title: Med Mol Morphol 41 Pages: 179-182
  • Peer Reviewed
• [Journal Article] A rare case of coexistence of pulmonary adenocarcinoma with Langerhans' cell histiocytosis. (2008)
  • Author(s): Ohtsuki Y, Uomoto M, Hachisuka Y, Kato M, Iguchi M, Lee GH, Furihata M
  • Journal Title: Med Mol Morphol 41 Pages: 175-178
  • Peer Reviewed
• [Journal Article] Sarcomatoid acquired cystic disease-associated renal cell carcinoma. (2008)
  • Author(s): Kuroda N, Tamura M, Taguchi T, Tominaga A, Hes O, Michal M, Ohara M, Hirouchi T, Mizuno K, Hayashi Y, Shuin T, Lee GH
  • Journal Title: Histol Histopathol 23 Pages: 1327-1331
  • Peer Reviewed
• [Journal Article] Immunohistochemical localisation of surfactant proteins A and D, and KL-6 in pulmonary alveolar proteinosis. (2008)
  • Author(s): Ohtsuki Y, Kobayashi M, Yoshida S, Kishimoto N, Kubo K, Yokoyama A, Lee GH, Furihata M
  • Journal Title: Pathology 40 Pages: 536-539
  • Peer Reviewed
• [Journal Article] Micropapillary component of urothelial carcinoma detected in transurethral resection of bladder tumor (TUR-BT) tissues : a case report. (2008)
  • Author(s): Ohtsuki Y, Ochi K, Okada Y, Kato M, Lee GH, Furihata M
  • Journal Title: Med Mol Morphol 41 Pages: 113-116
  • Peer Reviewed
• [Journal Article] Basal-like carcinoma of the breast : further evidence of the possibility that most metaplastic carcinomas may be actually basal-like carcinomas. (2008)
  • Author(s): Kuroda N, Fujishima N, Inoue K, Ohara M, Hirouchi T, Mizuno K, Hayashi Y, Lee GH
  • Journal Title: Med Mol Morphol 41 Pages: 117-120
  • Peer Reviewed
• [Journal Article] Significance of D2-40 expression in the diagnosis of gastrointestinal stromal tumor. (2008)
  • Author(s): Kuroda N, Tanida N, Oonishi K, Inoue K, Ohara M, Mizuno K, Taguchi T, Hayashi Y, Hanazaki K, Lee GH
  • Journal Title: Med Mol Morphol 41 Pages: 109-112
  • Peer Reviewed
• [Journal Article] Multiple minute nests of incidentally detected paraganglionic cells associated with urothelial carcinoma of the urinary bladder in a 73 year-old woman. (2008)
  • Author(s): Ohtsuki Y, Ochi K, Okada Y, Lee GH, Furihata M
  • Journal Title: Med Mol Morphol 41 Pages: 62-65
  • Peer Reviewed
• [Journal Article] Possible identification of third stromal component in extraadrenal paraganglioma : myofibroblast in fibrous band and capsule. (2008)
  • Author(s): Kuroda N, Tamura M, Ohara M, Hirouchi T, Mizuno K, Miyazaki E, Hayashi Y, Lee GH
  • Journal Title: Med Mol Morphol 41 Pages: 59-61
  • Peer Reviewed
• [Journal Article] The local injection of peritoneal macrophages induces neovascularization in rat ischemic hind limb muscles. (2008)
  • Author(s): Hirose N, Maeda H, Yamamoto M, Hayashi Y, Lee GH, Chen L, Radhakrishnan G, Rao P, Sasaguri S
  • Journal Title: Cell Transplant 17 Pages: 211-222
  • Peer Reviewed
• [Journal Article] Histochemical demonstration of aluminum and iron deposition in pulmonary bony tissues in three cases of diffuse pulmonary ossification. (2008)
  • Author(s): Ohtsuki Y, Yamanaka A, Ohyama H, Yamada E, Terada N, Fujita J, Lee GH, Furihata M
  • Journal Title: Histol Histopathol 23 Pages: 137-141
  • Peer Reviewed
• [Journal Article] Carcinoid tumor of the renal pelvis : consideration on the histogenesis. (2008)
  • Author(s): Kuroda N, Katto K, Tamura M, Shiotsu T, Hes O, Michal M, Nagashima Y, Ohara M, Hirouchi T, Mizuno K, Hayashi Y, Lee GH
  • Journal Title: Pathol Int 58 Pages: 51-54
  • Peer Reviewed
• [Journal Article] Inhibition of neointimal hyperplasia development by MCI-186 is correlated with downregulation of nuclear factor-kappaB pathway. (2008)
  • Author(s): Radhakrishnan G, Suzuki R, Maeda H, Yamamoto M, Hirose N, Gopalrao RK, Lee GH, Hayashi Y, Rao P, Sasaguri S
  • Journal Title: Circ J 72 Pages: 800-806
  • Peer Reviewed
• [Presentation] マウスを利用した肺発がん感受性の研究 -マウスからヒトヘ、ヒトからマウスヘ- (2008)
  • Author(s): 李康弘, 林芳弘
  • Organizer: 第97回 日本病理学会総会
  • Place of Presentation: 金沢(石川県立音楽堂)
  • Year and Date: 2008-05-16