Functional analysis of tumor metastasis promoting gene induced by p27-downregulation

• Project/Area Number: 19370083
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cell biology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: KITAGAWA Masatoshi Hamamatsu University School of Medicine, 医学部, 教授 (50294971)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2008: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2007: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
• Keywords: 癌 / p27kip1 / 転移 / Gタンパク共役型受容体 / 細胞周期 / p27Kip1

Research Abstract

細胞周期抑制因子であるCDK阻害タンパク質p27Kip1の分解亢進が広範囲の癌で起こっており、p27の発現量低下は癌の予後と深く相関している。しかしながらその原因およびメカニズムは不明であった。我々はそれを解明すべく、p27の発現低下モデル細胞(p27-hKO)を作成し、マイクロアレイによる発現遺伝子解析を行った。その結果、機能未知の7回幕貫通Gタンパク共役型受容体GPR48/LGR4がp27の発現低下で発現が増加することを見出した。このGPR48の強制発現により癌細胞の浸潤能、肺転移は著明に亢進し、ノックダウンすることによりこの細胞の浸潤能は抑制され、肺転移能が低下した。またヒト大腸癌検体においてリンパ節転移とGPR48の発現亢進が相関していた。以上よりGPR48はp27の発現低下によって誘導される新たな浸潤転移促進遺伝子であることが判明した。またGPR48トランスジェニックマウスを作成し、個体レベルでの機能解析を試みたが、タンパク質としての発現が低く、改良が必要と考えられた。

Research Products

• [Journal Article] TSU68 prevents liver metastasis of colon cancer xenografts by modulating the pre-metastatic niche (2008)
  • Author(s): Yamamoto, M., Kikuchi, H., Ohta, M., Kawabata, T., Hiramatsu, Y., Kondo, K., Baba, M,. Kamiya, K., Tanaka, T., Kitagawa M.and Konno H.
  • Journal Title: Cancer Res 68 Pages: 9754-9762
• [Journal Article] Intrarenal RAS activity and urinary angiotensinogen excretion in anti-thymocyte serum nephritis rats (2008)
  • Author(s): Ohashi, N., Yamamoto, T., Huang, Y., Misaki, T., Fukasawa, H., Suzuki, H.,Togawa, A., Suzuki, S., Fujigaki, Y., Nakagawa, T., Nakamura, Y., Suzuki, F., Kitagawa, M., Hishida, A.
  • Journal Title: Am J.Physiol Renal Physiol 295 Pages: 1512-1518
• [Journal Article] Novel insights into FGD3, a putative GEF for Cdc42, that undergoes SCF^<FWD1/・-TrCP>-mediated proteasomal degradation analogous to that of its homologue FGD1 but regulates cell morphology and motility differently from FGD1 (2008)
  • Author(s): Hayakawa, M., Matsushima, M., Hagiwara, H., Oshima, T., Fujino, T., Ando, K., Kikugawa, K., Tanaka, H., Miyazawa, K.and Kitagawa, M.
  • Journal Title: Genes to Cells 13 Pages: 329-442
• [Journal Article] Pirh2 interacts with and ubiquitylates signal recognition particle receptor beta subunit (2008)
  • Author(s): Abe K, Hattori T, Isobe T, Kitagawa K, Oda T, Uchida C, Kitagawa, M
  • Journal Title: Biomed Res 29 Pages: 53-60
  • NAID: 130004470702
• [Journal Article] Stress via p^<53> pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells (2008)
  • Author(s): Kurata, K., Yanagisawa, R., Ohira, M. Kitagawa, M., Nakagawara, A., Kamijo, T.
  • Journal Title: Oncogene 27 Pages: 741-754
• [Journal Article] Regulation of TGF-beta signaling by Smads and its roles in tissue fibrosis (2008)
  • Author(s): Fukasawa, H., Yamamato, T., Kitagawa, M.and Hishida, A.
  • Journal Title: Current signal transduction therapy(review article) 3 Pages: 1-6
• [Journal Article] Novel insights into FGD3, a putative GEF for Cdc42, that undergoes SCF-FWD1/β-TRCP-mediated proteasomal degradation analogous to that of its homologue FGD1 but regulates cell morphology and motility differently from FGD1. (2008)
  • Author(s): Hayakawa, M., et al.
  • Journal Title: Genes to Cells 13 Pages: 329-442
  • Peer Reviewed
• [Journal Article] Intrarenal RAS activity and urinary angiotensinogen excretion in anti-thymocyte serum nephritis rats. (2008)
  • Author(s): Ohashi, N., et al.
  • Journal Title: Am J. Physiol Renal Physiol. 295
  • Peer Reviewed
• [Journal Article] TSU68 prevents liver metastasis of colon cancer xenografts bymodulating the pre-metastatic niche. (2008)
  • Author(s): Yamamoto, M., et al.
  • Journal Title: Cancer Res. 68 Pages: 9754-9762
  • Peer Reviewed
• [Journal Article] Pirh2 interacts with and ubiquitylates signal recognition particle recept or beta subunit (2008)
  • Author(s): Abe, K., et. al.
  • Journal Title: Biomed Res. 29 Pages: 53-60
  • Peer Reviewed
• [Journal Article] Pirh2 Promotes Ubiquitin-Dependent Degradation of the CDK Inhibitor p27Kip1 (2007)
  • Author(s): Hattori, T., Isobe, T., Abe, K., Kikuchi, H., Kitagawa, K., Oda, T., Uchida, C.and Kitagawa, M.
  • Journal Title: Cancer Research 67 Pages: 10789-10795
• [Journal Article] Critical and functional regulation of CHOP(C/EBP homologous protein)through the N-terminal portion (2007)
  • Author(s): Ohoka, N., Hattori, T., Kitagawa, M., Onozaki, K. and Hayashi H.
  • Journal Title: J Biol Chem 282 Pages: 35687-35694
• [Journal Article] Contribution of Extracellular Signal-Regulated Kinases to the IL-1-induced Growth Inhibition of Human Melanoma Cells A375 (2007)
  • Author(s): Arakawa, T., Yamamura, T., Hattori, T., Hayashi H., Mori, A., Yoshida, A., Uchida, C., Kitagawa, M.and Onozaki, K.
  • Journal Title: International Immunopharmacology 8 Pages: 80-89
• [Journal Article] Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in aceruloplasminemia (2007)
  • Author(s): Kono, S., Suzuki, H., Oda, T., Takahashi, Y., Shirakawa, K., Takahashi, Y., Kitagawa, M.and Miyajima, H.
  • Journal Title: J.Hepatology 47 Pages: 844-850
• [Journal Article] Effect of loss of heterozygosity of the c-kit gene on prognosis after hepatectomy for metastatic liver gastrointestinal stromal tumors (2007)
  • Author(s): Kikuchi, H., Yamamoto, M., Hiramatsu, Y., Baba, M., Ohta, M., Kamiya, K., Tanaka, T., Suzuki, S., Sugimura, H., Kitagawa, M., Kanai, T., Kitayama, Y., Kanda, T., Nishikura, K. and Konno, H
  • Journal Title: Cancer Sci 98 Pages: 1734-1739
  • NAID: 10020119012
• [Journal Article] ARA54 is involved in transcriptional regulation of the cyclin D1 gene in human cancer cells (2007)
  • Author(s): Kikuchi, H., Uchida, C., Hattori, T., Isobe, T., Hiramatsu, Y., Kitagawa, K., Oda, T., Konno, H.and Kitagawa, M
  • Journal Title: Carcinogenesis 28 Pages: 1752-1758
• [Journal Article] Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice (2007)
  • Author(s): Suzuki, S., Fukasawa, H., Kitagawa, K., Uchida, C., Hattori, T., Isobe, T., Oda, T., Misaki, T., Ohashi, N., Nakayama, K., Nakayama, K.I., Hishida, A., Yamamoto, T.and Kitagawa, M.
  • Journal Title: Am.J.Pathol 171 Pages: 473-483
• [Journal Article] Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between pRB and E2F-1 after DNA damage (2007)
  • Author(s): Inoue, Y., Kitagawa, M.and Taya, Y.
  • Journal Title: EMBO J 26 Pages: 2083-2093
• [Journal Article] Genetically engineered neural stem cells migrate and suppress glioma cell growth at distant intracranial sites (2007)
  • Author(s): Li, S., Gao, Y., Tokuyama, T.,Yamamoto, J., Yokota, N., Yamamoto, S., Terakawa, S., Kitagawa, M.and Namba, H.
  • Journal Title: Cancer Letters 251(2) Pages: 220-227
• [Journal Article] Pirh2 Promotes Ubiquitin-Dependent Degradation of the CDK Inhibitor p27Kip1 (2007)
  • Author(s): Hattori, T., et. al.
  • Journal Title: Cancer Res. 67 Pages: 10789-10795
  • Peer Reviewed
• [Journal Article] ARA54 is involved in transcriptional regulation of the cyclin D1 gene in human cancer cells (2007)
  • Author(s): Kikuchi, H., et. al.
  • Journal Title: Carcinogesis 28 Pages: 1752-1758
  • Peer Reviewed
• [Journal Article] Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice (2007)
  • Author(s): Suzuki, S., et. al.
  • Journal Title: Am.J.Pathol 171 Pages: 473-483
  • Peer Reviewed
• [Journal Article] Effect of loss of heterozygosity of the c-kit gene on prognosis after hepa tectomy for metastatie liver gastrointestinal stromal tumors (2007)
  • Author(s): Kikuchi, H., et. al.
  • Journal Title: Cancer Sci. 98 Pages: 1734-1739
  • Peer Reviewed
• [Journal Article] Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in aceruloplasminemia (2007)
  • Author(s): Kono, S., et. al.
  • Journal Title: J.Hepatologp 47 Pages: 844-850
  • Peer Reviewed
• [Journal Article] Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregul ation in doxorubicin-treated neuroblastoma cells (2007)
  • Author(s): Kurata, K., et. al.
  • Journal Title: Oncogene 27 Pages: 741-754
  • Peer Reviewed
• [Journal Article] Critical and functional regulation of CHOP(C/EBP hoinologous protein)through the N-terminal portion (2007)
  • Author(s): Ohoka, N., et. al.
  • Journal Title: J Biol Chem 282 Pages: 35687-35694
  • Peer Reviewed
• [Journal Article] Contribution of Extracellular Signal-Regulated Kinases to the IL-1-induced Growth Inhibition of Human Melanoma Cells A375 (2007)
  • Author(s): Arakawa, T., et. al.
  • Journal Title: Internetional Immunopharmacology 8 Pages: 80-89
  • Peer Reviewed
• [Presentation] GPR48による癌転移機構の解析 (2008)
  • Author(s): 磯部智康, 島田真衣, 劉寧, 北川恭子, 鈴木小由里, 小田敏明, 服部隆行, 内田千晴, 北川雅敏
  • Organizer: 第31回日本分子生物学会、第81回日本生化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-10
• [Presentation] タンパク質過剰発現誘導性小胞体の構造と機能 (2008)
  • Author(s): 小田敏明, 服部隆行, 磯部智康、北川恭子, 内田千晴, 横田貞記 北川雅敏
  • Organizer: 第31回日本分子生物学会、第81回日本生化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] タンパク質過剰発現誘導性小胞体の構造と機能 (2008)
  • Author(s): 小田敏明, 等
  • Organizer: 第31回日本分子生物学会、第81回日本生化学会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] 細胞周期制御分子p27のユビキチン依存的分解機構と病態 (2007)
  • Author(s): 北川雅敏
  • Organizer: 第30回日本分子生物学会第80回日本生化学会合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-12
• [Presentation] Novel regulatory mechanisms of Cyclin D1 expression (2007)
  • Author(s): Kitagawa, M. et.al.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-05
• [Presentation] Novel regulatory mechanisms of Cyclin Dl expression (2007)
  • Author(s): Kitagawa, M., et. al.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-05
• [Presentation] 癌関連核内因子のユビキチン依存的制御機構 (2007)
  • Author(s): 北川雅敏
  • Organizer: Nuclear Signaling JAPAN 2007シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-07-13
• [Remarks]
  • URL: http://www2.hama-med.ac.jp/w1a/bio1/index-j.html
• [Remarks]
  • URL: http://www2.hama-med.ac.jp/w1a/bio1/index-j.html