p53による時間、空間的な遺伝子発現制御機構の解明

• Project Area: Integrative Systems Understanding of Cancer for Advanced Diagnosis, Therapy and Prevention
• Project/Area Number: 25134707
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: The University of Tokyo
• Principal Investigator: 松田 浩一 東京大学, 医科学研究所, 准教授 (90401257)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: p53 / RNA sequence

Outline of Annual Research Achievements

ヒトの癌の約半数で変異が認められる癌抑制遺伝子p53は転写因子として機能し、様々なDNAダメージによって活性化され、100以上の下流遺伝子を発現誘導する事が知られている。p53+/+, p53-/-マウスに全身照射を行い各臓器でのRNA sequenceを行う事で、p53を介した発癌抑制機構を個体レベルで明らかにする事が本研究の目的である。
放射線照射後のマウスより臓器の回収とRNAの評価を行い、24臓器、計276サンプルについて、次世代シークエンサーによるRNA sequenceを行った。さらにこの解析結果を元に、臓器別の下流遺伝子の抽出を行った。
p53により最も遺伝子発現に影響を受ける臓器は胸腺で、約3000遺伝子が2倍以上に発現誘導され、約1500遺伝子が1/2以下に発現抑制された。また脾臓、骨髄もp53による遺伝子変化が顕著であった。一方精巣や脳などの組織は放射線の影響を受けにくく、p53の活性化、下流遺伝子の誘導には顕著な臓器特異性があることが明らかとなった。
平行して各臓器におけるp53標的分子の同定と機能解析を進めている。各臓器で誘導される遺伝子について、対応するヒト癌細胞株もしくは正常細胞株を用いて、発現誘導を検討した。またがん組織における遺伝子発現データを元に、p53の変異と有意な相関を示す遺伝子を抽出している。現在、肝臓、骨、消化管（食道、胃、小腸、大腸）、乳腺、肺については、複数の下流候補を抽出し、p53結合配列の同定や細胞増殖に及ぼす影響、発がんに制御における意義などの検討を進めている。これらの解析によって、ヒト、マウスに共通してp53により誘導され、またp53変異を有するがん組織において発現が低下する遺伝子について、有力なp53の下流遺伝子候補と考えさらなる機能解析を進めている。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Late Cornified Envelope Group I, a novel target of p53, regulates PRMT5 activity. (2014)
  • Author(s): Deng Z, Matsuda K, Tanikawa C, Lin J, Furukawa Y, Hamamoto R, Nakamura Y.
  • Journal Title: Neoplasia Volume: 16 Issue: 8 Pages: 656-664
  • DOI: 10.1016/j.neo.2014.07.008
  • Peer Reviewed
• [Journal Article] Downregulation of the tumor suppressor HSPB7, involved in the p53 pathway, in renal cell carcinoma by hypermethylation. (2014)
  • Author(s): Lin J, Deng Z, Tanikawa C, Shuin T, Miki T, Matsuda K, Nakamura Y.
  • Journal Title: Int J Oncol Volume: 44 Issue: 5 Pages: 1490-1498
  • DOI: 10.3892/ijo.2014.2314
  • Peer Reviewed
• [Journal Article] Antitumor Activity and Induction of TP53-Dependent Apoptosis toward Ovarian Clear Cell Adenocarcinoma by the Dual PI3K/mTOR Inhibitor DS-7423. (2014)
  • Author(s): Kashiyama T, Oda K, Ikeda Y, Shiose Y, Hirota Y, Inaba K, Makii C, Kurikawa R, Miyasaka A, Koso T, Fukuda T, Tanikawa M, Shoji K, Sone K, Arimoto T, Wada-Hiraike O, Kawana K, Nakagawa S, Matsuda K, McCormick F, Aburatani H, Yano T, Osuga Y, Fujii T
  • Journal Title: PLoS One Volume: 9 Issue: 2 Pages: e87220-e87220
  • DOI: 10.1371/journal.pone.0087220
  • Peer Reviewed
• [Journal Article] Downregulation of the tumor suppressor HSPB7, involved in the p53 pathway, in renal cell carcinoma by hypermethylation. (2014)
  • Author(s): J. Lin, Z. Deng, C. Tanikawa, T. Shuin, T. Miki, K. Matsuda, Y. Nakamura
  • Journal Title: Int J oncol Volume: 44 Pages: 1490-1498
  • Peer Reviewed
• [Journal Article] Impact of PSCA variation on gastric ulcer susceptibility. (2013)
  • Author(s): C. Tanikawa, K. Matsuo, M. Kubo, A. Takahashi, H. Ito, H. Tanaka, Y. Yatabe, K. Yamao, N. Kamatani, K. Tajima, Y. Nakamura, K. Matsuda
  • Journal Title: Plos one Volume: 8 Issue: 5 Pages: e63698-e63698
  • DOI: 10.1371/journal.pone.0063698
  • Peer Reviewed
• [Journal Article] Identification of a Functional Variant in the MICA Promoter Which Regulates MICA Expression and Increases HCV-Related Hepatocellular Carcinoma Risk. (2013)
  • Author(s): Lo PH, Urabe Y, Kumar V, Tanikawa C, Koike K, Kato N, Miki D, Chayama K, Kubo M, Nakamura Y, Matsuda K.
  • Journal Title: PLoS One. Volume: 8 Issue: 4 Pages: e61279-e61279
  • DOI: 10.1371/journal.pone.0061279
  • Peer Reviewed
• [Presentation] Screening of p53-targets in gynecological organs (2014)
  • Author(s): Makoto Takeuchi, Chizu Tanikawa, Jinichi Mori, Paulisally Lo, Tomoyuki Koguchi, Yusuke Tsuda, Ryuta Yamamoto, Katsutoshi Oda, Tomoyuki Fujii, Yusuke Nakamura,, Koichi Matsuda
  • Organizer: The 73rd Annual meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Regulation of amino acid metabolism by p53 (2014)
  • Author(s): Paulisally Hau Yi Lo, Chizu Tanikawa, Yusuke Nakamura, Koichi Matsuda
  • Organizer: The 73rd Annual meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Regulation of iron homeostasis by p53-ISCU pathway (2014)
  • Author(s): Yuki Funauchi, Chizu Tanikawa, Paulisally Lo, Masami Tanaka, Jinichi Mori, Yataro Daigo, Atsushi Takano, Yohei Miyagi, Yusuke Nakamura, Koichi Matsuda
  • Organizer: The 73rd Annual meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Regulation of cytoskeleton by p53 (2014)
  • Author(s): Mori Jinichi, Chizu Tanikawa, Paulisally HY Lo, Yuki Funauchi, Yusuke Nakamura, Koichi Matsuda
  • Organizer: The 73rd Annual meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Regulation of gene expression by p53 in bone and cartilage tissues (2014)
  • Author(s): Yusuke Tsuda, Chizu Tanikawa, Jinichi Mori , Paulisally Lo , Tomoyuki koguchi, Makoto Takeuchi, Ryuta Yamamoto, Hirotaka Kawano, Sakae Tanaka, Yusuke Nakamura, Koichi Matsuda
  • Organizer: The 73rd Annual meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Identification of novel p53 targets in the gastrointestinal tract (2014)
  • Author(s): Ryuta Yamamoto,, Chizu Tanikawa, Jinich Mori, Makoto Takeuchi, Yusuke Tsuda, Tomoyuki Koguchi, Satoru Miyano, Seiya Imoto, Rui Yamaguchi, Hiroharu Yamashita, Yasuyuki Seto, Yusuke Nakamura, Koichi Matsuda
  • Organizer: The 73rd Annual meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Screening of novel p53 targets by RNA sequence analysis (2014)
  • Author(s): Tomoyuki Koguchi, Chizu Tanikawa, Jinichi Mori, Makoto Takeuchi, Yusuke Tsuda, Ryuta Yamamoto, Satoru Miyano, Seiya Imoto, Rui Yamaguchi, Yoshiyuki Kojima, Yusuke Nakamura, Koichi Matsuda
  • Organizer: The 73rd Annual meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] The roles of gene-environmental interaction in human carcinogenesis (2013)
  • Author(s): Koichi Matsuda Michiaki Kubo Chizu Tanikawa, Yusuke Nakamura
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] The roles of gene-environmental interaction in human carcinogenesis (2013)
  • Author(s): Koichi Matsuda Michiaki Kubo Chizu Tanikawa, Yusuke Nakamura
  • Organizer: AACR-JCA joint symposium
  • Place of Presentation: 幕張
  • Invited