Role of the RNA-primase GANP in cancer development

• Project/Area Number: 17013069
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kumamoto University
• Principal Investigator: SAKAGUCHI Nobuo Kumamoto University, 大学院・生命科学研究部, 教授 (70192086)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥37,200,000 (Direct Cost: ¥37,200,000); Fiscal Year 2009: ¥7,500,000 (Direct Cost: ¥7,500,000); Fiscal Year 2008: ¥7,500,000 (Direct Cost: ¥7,500,000); Fiscal Year 2007: ¥7,500,000 (Direct Cost: ¥7,500,000); Fiscal Year 2006: ¥7,500,000 (Direct Cost: ¥7,500,000); Fiscal Year 2005: ¥7,200,000 (Direct Cost: ¥7,200,000)
• Keywords: 発がん / 老化 / RNA輸送 / 乳癌 / プライマーゼ / 遺伝子 / 癌 / 細胞・組織 / ストレス / 生体分子 / 胚中心 / 細胞 / ホジキン病 / 転移 / 病理診断 / がん抑制分子 / B細胞 / 悪性黒色腫

Research Abstract

Antibody response to T cell dependent antigens accompanies somatic hypermutation of immunoglobulin Variable region genes, which needs to be regulated precisely and safely. We studied the role of a molecule named GANP up-regualted in germinal center B cells in the peripheral lymphoid organs. GANP is essential for affinity maturation of the antigen specific B cells. Impairment of GANP function caused lymphomas and mammary gland tumors in mice. We showed that the GANP impairments are associated with tumor development in humans and provided the information regarding spontaneous cancer development during inflammation..

Research Products

• [Journal Article] GANP-mediated recruitment of activation-induced cytidine deaminase to cell nuclei and to immunoglobulin Variable region DNA. (2010)
  • Author(s): Kazuhiko Maeda, Shailendra Kumar Singh, Kazufumi Eda, Masahiro Kitabatake, Phuong Pham, Myron F. Goodman, Nobuo Sakaguchi(Corresponding author)
  • Journal Title: J. Biol. Chem. (on line)
  • Peer Reviewed
• [Journal Article] Germinal center-associated nuclear protein, a human homologue of SAC3, is necessary for centromere cohesion and sister-chromatid exchange during mitosis. (2010)
  • Author(s): Nobukazu Okamoto, Kazuhiko Kuwahara, Kazutaka Ohta, Masahiro Kitabatake, Hideya Igarashi, Katsumasa Takagi, Hiroshi Mizuta, Eisaku Kondo, Nobuo Sakaguchi
  • Journal Title: Genes to Cells 15 Pages: 471-483
  • Peer Reviewed
• [Journal Article] Germinal center-associated nuclear protein (GANP) is involved in mRNA export of Shugoshin-1 required for centromere cohesion and in sister-chromatid exchange. (2010)
  • Author(s): Okamoto N
  • Journal Title: Genes to Cells (In press)
  • Peer Reviewed
• [Journal Article] Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity. (2010)
  • Author(s): Mahsson R
  • Journal Title: Blood 115 Pages: 2060-2609
  • Peer Reviewed
• [Journal Article] A Flt3- and Ras-dependent pathway primes B cell development by inducing a state of IL-7 responsiveness. (2010)
  • Author(s): Li LX.
  • Journal Title: Journal of Immunology 184 Pages: 1728-1736
  • Peer Reviewed
• [Journal Article] Decreased expression of germinal center-associated nuclear protein is involved in chromosomal instability in malignant gliomas. (2009)
  • Author(s): Kazutaka Ohta, Kazuhiko Kuwahara, Zhenhuan Zhang, Keishi Makino, Yoshihiro Komohara, Hideo Nakamura, Jun-Ichi Kuratsu, Nobuo Sakaguchi
  • Journal Title: Cancer Sci. 100 Pages: 2069-2076
  • NAID: 10027196786
  • Peer Reviewed
• [Journal Article] Cholangiocarcinomas associated with long-term inflammation express the activation-induced cytidine deaminase and germinal center-associated nuclear protein involved in immunoglobulin V-region diversification (2009)
  • Author(s): Waraporn Chan-On, Kazuhiko Kuwahara, Naoya Kobayashi, Kazutaka Ohta, Tatsuya Shimasaki, Banchob Sripa, Chanvit Leelayuwat, Nobuo Sakaguchi
  • Journal Title: Int. J. Oncol. 35,2 Pages: 287-295
  • Peer Reviewed
• [Journal Article] GANP suppresses the arginine methyltransferase PRMT5 regulating IL-4-mediated STAT6-signaling to IgE production in B cells. (2009)
  • Author(s): Hideya Igarashi, Kazuhiko Kuwahara, Mikoto Yoshida, Yan Xing, Kazuhiko Maeda, Kouji Nakajima, Nobuo Sakaguchi
  • Journal Title: Mol. Immunol. 46 Pages: 1031-1041
  • Peer Reviewed
• [Journal Article] Decreased expression of germinal center-associated nuclear protein is involved in chromosomal instability in malignant gliomas. (2009)
  • Author(s): Ohta K
  • Journal Title: Cancer Science. 100 Pages: 2069-2076
  • Peer Reviewed
• [Journal Article] Cholangiocarcinomas associated with long-term inflammation express the activation-induced cytidine deaminase and germinal center-associated nuclear protein involved in immunoglobulin V-region diversification. (2009)
  • Author(s): Chan-On W
  • Journal Title: International Journal of Oncology 35 Pages: 287-295
  • Peer Reviewed
• [Journal Article] Generation of high affinity monoclonal antibodies for the prevention of HIV infection. (2009)
  • Author(s): Sakaguchi N
  • Journal Title: Recent Patent of DNA Gene Sequence 3 Pages: 88-95
  • Peer Reviewed
• [Journal Article] GANP suppresses the arginine methyltransferase PRMT5 regulating IL-4-mediated STAT-6signaling to IgE production in B cells (2009)
  • Author(s): Igarashi H
  • Journal Title: Mol Immunol 46(6) Pages: 1031-41
  • Peer Reviewed
• [Journal Article] The immature B-cell subpopulation with low RAG1 expression is increased in the autoimmune New Zealand Black mouse (2009)
  • Author(s): Toda T
  • Journal Title: Eur J Immunol 39(2) Pages: 600-11
  • Peer Reviewed
• [Journal Article] Germinal center B-cell associated DNA hypomethylation at transcriptional regions of the AID gene. (2008)
  • Author(s): Satoru Fujimura, Takeshi Matsui, Kazuhiko Kuwahara, Kazuhiko Maeda, Nobuo Sakaguchi
  • Journal Title: Mol. Immunol. 45 Pages: 1712-1719
  • Peer Reviewed
• [Journal Article] Protein phosphatase subunit G5PR that regulates the JNK-mediated apoptosis signal is essential for the survival of CD4 and CD8 double-positive thymocytes. (2008)
  • Author(s): Xing Y.
  • Journal Title: Molecular Immunology 45 Pages: 2028-2037
  • Peer Reviewed
• [Journal Article] Germinal center B-cell-associated DNA hypomethylation attranscriptional regions of the AID gene. (2008)
  • Author(s): Fujimura S.
  • Journal Title: Molecular Immunology 45 Pages: 1712-1719
  • Peer Reviewed
• [Journal Article] GANP suppresses DNA recombination, measured by direct-repeat b-galactosidase gene construct, but does not suppress the type of recombination applying to immunoclpbulin genes in mammalian cells. (2007)
  • Author(s): Mikoto Yoshida, Kazuhiko Kuwahara, Tatsuya Shimasaki, Naomi Nakagata, Masao Matsuoka, Nobuo Sakaguchi
  • Journal Title: Genes Cells 12 Pages: 1205-1213
  • Peer Reviewed
• [Journal Article] GANP suppresses DNA recombination, measured by direct-repeat beta-galactosidase gene construct, but does not suppress the type of recombination applying to immunoglobulin genes in mammailian cells. (2007)
  • Author(s): Yoshida M.
  • Journal Title: Genes to Cells 12 Pages: 1205-1213
  • Peer Reviewed
• [Journal Article] Increased expression of germinal center-associated nuclear protein (GANP) is associated with malignant transformation of melanocytes. (2006)
  • Author(s): Toshiro Kageshita, Kazuhiko Kuwahara, Masahiro Oka, Donglai Ma, Tomomich Ono, Nobuo Sakaguchi
  • Journal Title: J. Dermatol. Sci 42 Pages: 55-63
  • NAID: 10020550048
  • Peer Reviewed
• [Journal Article] BCR-crosslinking induces a transcription of protein phosphatase component G5PR that is required for mature B-cell survival. (2006)
  • Author(s): Huq Faisal Muhmudul Ronny et al.
  • Journal Title: Biochemical and Biophysics Research Communication 340 Pages: 338-346
• [Journal Article] Production of two novel monoclonal antibodies that distinguish mouse lymphatic and blood vascular endothelial cells. (2006)
  • Author(s): Taichi Ezaki et al.
  • Journal Title: Anatomy and Embryology 211 Pages: 379-393
• [Journal Article] Regulation of CaMKII by alpha4/PP2Ac contributes to learning and memory. (2006)
  • Author(s): Takeshi Yamashita et al.
  • Journal Title: Brain Research 1082 Pages: 1-10
• [Journal Article] Increased expression of germinal center-associated nuclear protein (GANP) is associated with malignant transformation of melanocytes. (2006)
  • Author(s): Toshiro Kageshita et al.
  • Journal Title: Journal of Dermatological Science 42 Pages: 55-63
• [Journal Article] Increased expression of germinai center-associated nuclear protein (GANP) is associated with malignant transformation of melanocytes. (2006)
  • Author(s): Toshiro Kageshita et al.
  • Journal Title: Journal of Dermatological Science 42 Pages: 55-63
• [Journal Article] Cutting Edge: Double-stranded DNA breaks in the immunoglobulin V-region gene were detected at lower frequency in affinity-maturation impeded GANP-/- mice. (査読有り) J. Immunol. (2005)
  • Author(s): Yousuke Kawatani, Hideya Igarashi, Takeshi Matsui, Kazuhiko Kuwahara, Satoru Fujimura, Nobukazu Okamoto, Katsumasa Takagi, Nobuo Sakaguchi
  • Journal Title: J. Immunol. 175 Pages: 5615-5618
  • Peer Reviewed
• [Journal Article] Protein phosphatase subunit G5PR is needed for inhibition of BCR-induced apoptosis. (2005)
  • Author(s): Yan Xing, Hideya Igarashi, Xiaodang, Wang, Nobuo Sakaguchi
  • Journal Title: J. Exp. Med. 202 Pages: 707-719
  • Peer Reviewed
• [Journal Article] Increased expression of GANP RNA-primase is associated with lymphomagenesis. (2005)
  • Author(s): Satoru Fujimura, Yan Xing, Motohiro Takeya, Yasuyuki Yamashita, Koichi Ohshima, Kazuhiko Kuwahara, Nobuo Sakaguchi
  • Journal Title: Cancer Res. 65 Pages: 5925-5934
  • Peer Reviewed
• [Journal Article] Generation of high-affinity antibody against T cell-dependent antigen in ganp gene-transgenic mouse. (2005)
  • Author(s): Nobuo Sakaguchi, Tetsuya Kimura, Shuzo Matsushita, Satoru Fujimura, Junji Shibata, Masatake Araki, Tamami Sakamoto, Chiemi Minoda, Kazuhiko Kuwahara
  • Journal Title: J. Immunol 174 Pages: 4485-4494
  • Peer Reviewed
• [Journal Article] BCR-crosslinking induces a transcription of protein phosphatase component G5PR that is required for mature B-cell survival. (2005)
  • Author(s): Huq Faisal Mhumudul Ronny et al.
  • Journal Title: Biochemical and Biophysics Research Communication 340 Pages: 338-346
• [Journal Article] Cutting edge : double-stranded DNA breaks in the IgV region gene were detected at lower frequency in affinity-maturation impeded GANP-/-mice. (2005)
  • Author(s): Yosuke Kawatani et al.
  • Journal Title: Journal of Immunology 175 Pages: 5615-5618
• [Journal Article] Protein phosphatase subunit G5PR is needed for inhibition of B cell receptor-induced apoptosis. (2005)
  • Author(s): Yan Xing et al.
  • Journal Title: Journal of Experimental Medicine 202 Pages: 707-719
• [Journal Article] Increased Expression of GANP RNA-Primase Is Associated with Lymphomagenesis. (2005)
  • Author(s): Satoru Fujimura et al.
  • Journal Title: Cancer Research 65 Pages: 5925-5934
• [Journal Article] The heterodimer of alpha4 and PP2Ac is associated with S6 kinasel in B cells. (2005)
  • Author(s): Takeshi Yamashita et al.
  • Journal Title: Biochemical and Biophysics Research Communication 330 Pages: 439-445
• [Presentation] Molecular Mechanism of Immunoglobulin V-region Diversification and its Application in Medical Sciences. (2009)
  • Author(s): 阪口薫雄
  • Organizer: The 2009 FallConference of The Korean Association of Immunologists.
  • Place of Presentation: Charoen Thani Princess Hotel korea
  • Year and Date: 2009-11-10
• [Presentation] mRNA核外輸送機能低下と発癌 (2009)
  • Author(s): 桑原一彦
  • Organizer: 第13回日本がん免疫学会
  • Place of Presentation: 北九州国際会議場
• [Presentation] mRNA核外輸送分子GANP異常による乳癌発症 (2009)
  • Author(s): 阪口薫雄
  • Organizer: 第13回日本がん分子標的治療学会
  • Place of Presentation: ホテルクレメント徳島
• [Presentation] Critical role of GANP in nuclear export of mRNA involved in mammalian cell division (2009)
  • Author(s): 阪口薫雄
  • Organizer: 第68回日本癌学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 胚中心B細胞制御におけるGANPファミリー分子の役割 (2009)
  • Author(s): 桑原一彦
  • Organizer: 第39回日本免疫学会
  • Place of Presentation: 大阪国際会議場
• [Presentation] A role of GANP in the targeting of AID at IgV-region gene locus (2009)
  • Author(s): 前田和彦
  • Organizer: 第39回日本免疫学会
  • Place of Presentation: 大阪国際会議場
• [Presentation] GANP分子発現低下による姉妹染色分体接着異常とその発癌における役割 (2008)
  • Author(s): 桑原一彦
  • Organizer: がん分子標的治療研究会
  • Place of Presentation: 学術総合センター(東京)
• [Presentation] Occurrence of sporadic breast cancer is associated with decrease of GANP causing abnormal sister chromatid cohesion (2008)
  • Author(s): 桑原一彦
  • Organizer: 癌学会
  • Place of Presentation: 名古屋国際会議場(愛知)
• [Presentation] Functional differences between GANP and THP1 in B cell activation and development (2008)
  • Author(s): 桑原一彦
  • Organizer: 日本免疫学会
  • Place of Presentation: 京都国際会議場(京都)
• [Presentation] Molecular study of GANP in IgV-region gene diversification (2008)
  • Author(s): 前田和彦
  • Organizer: 日本免疫学会
  • Place of Presentation: 京都国際会議場(京都)
• [Presentation] Regulation of IgV region diversification by GANP (2007)
  • Author(s): Kazuhiko Maeda.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2007-10-05
• [Presentation] Protein phosphatase subunit G5PR is required for survival of CD4+CD8+double-positive thymocytes (2007)
  • Author(s): Yan Xing.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2007-10-05
• [Presentation] Characterization of ganp gene abnormality in human breast cancer (2007)
  • Author(s): Kazuhiko Kuwahara.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2007-10-03
• [Presentation] 非遺伝性散発性乳癌における胚中心関連GANP分子の発現異常 (2007)
  • Author(s): 桑原 一彦
  • Organizer: 第11回基盤的癌免疫研究会
  • Place of Presentation: 東京(鉄門記念講堂)
  • Year and Date: 2007-07-11
• [Presentation] 非遺伝性散発生乳癌におけるGANPの発現異常 (2007)
  • Author(s): 桑原 一彦
  • Organizer: 第11回がん分子標的治療研究会総会
  • Place of Presentation: 大阪(大阪国際交流センター)
  • Year and Date: 2007-07-06
• [Remarks]
  • URL: http://www.k-immu.jp/ja/
• [Remarks]
  • URL: http://www.k-irrimu.jp/ja/
• [Patent(Industrial Property Rights)] 胆管がん特異的糖鎖エピトープを認識するモノクローナル抗体 (2009)
  • Inventor(s): 阪口薫雄、桑原一彦、荒木令江、坂本珠美
  • Industrial Property Rights Holder: 財)くまもとテクノ産業財団
  • Industrial Property Number: 2009-025607
  • Filing Date: 2009-02-02
• [Patent(Industrial Property Rights)] GANP DNA(マウス) (2006)
  • Inventor(s): 阪口薫雄
  • Industrial Property Rights Holder: 財団法人くまもとテクノ産業財団
  • Filing Date: 2006-11-21
• [Patent(Industrial Property Rights)] GANPによる癌抑制遺伝子の活性化方法 (2006)
  • Inventor(s): 阪口薫雄
  • Industrial Property Rights Holder: 国立大学法人熊本大学
  • Industrial Property Number: 2006-189043
  • Filing Date: 2006-07-10
• [Patent(Industrial Property Rights)] 抗GANP抗体(マウス) (2005)
  • Inventor(s): 阪口薫雄
  • Industrial Property Rights Holder: 財団法人くまもとテクノ産業財団
  • Filing Date: 2005-09-13