Functional analyses of novel tumor suppressor genes by gene targeting

• Project/Area Number: 15590335
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: INOUE Hirokazu School of Medicine, Department of Microbiology, Associate Professor, 医学部, 助教授 (30176440)
• Co-Investigator(Kenkyū-buntansha): HARAGUCHI Seiki School of Medicine, Department of Microbiology, Research Associate, 医学部, 助手 (10324576)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: Tumor suppressor gene / Apoptosis / Knockout mouse / Drs

Research Abstract

The drs gene was originally isolated as a suppressor against v-src transformation.
Drs protein has one transmembrane domain and three consensus repeat called Sushi motif. Expression of drs mRNA was markedly downregulated in a variety of human cancer cell lines and tissues, suggesting that the drs gene acts as a tumor suppressor. In this study, we investigated the function of Drs and the mechanism of tumor suppression by this gene and obtained the following results.
(1)Drs induces apoptosis by a novel pathway mediated by ASY/Nogo-B/RTN-xS, caspase-12, caspase-9 and caspase-3 in human cancer cells.
(2)We investigated the tumor suppressor function in vivo of drs and its physiological roles in apoptosis by generating a gene-knockout mouse. Malignant tumors including lymphomas, lung adenocarcinomas, hepatomas, and sarcoma were generated in about 25% of 46 drs-knockout(KO)mice. No tumors were detected in all (23) wild-type mice examined at the same age.
(3)Re-introduction of drs by retrovirus vector into a lung cancer cell line derived from a lung adenocarcinoma of a drs KO mouse caused suppression of tumorigenicity in nude mouse and elevation of apoptosis mediated by activation of caspase-3.
(4)Drs KO MEF cells showed resistance to certain apoptosis-inducing reagent such as rapamycine and dexamethazone.
(5)Apoptosis was induced in glucose-depleted Drs KO MEF cells, suggesting the closstalk between Drs-induced apoptosis pathway and mTOR signal pathway.
These results idicate that the drs gene acts as a tumor suppressor in genesis of malignant tumors and that drs play a role in certain apoptotic pathways in physiological conditions.

Research Products

• [Journal Article] Rb1cc1 is critical for myoblast differentiation through Rb1 regulation. (2005)
  • Author(s): Watanabe, R. et al.
  • Journal Title: Virchows Arch. 446(in press)
• [Journal Article] Periostin is down-regulated in high grade human bladder cancers and Suppresses in vitro cell invasineness and in vivo metastasis of cancer cells. (2005)
  • Author(s): Kim, C.J.et al.
  • Journal Title: Int.J. Cancer (in press)
• [Journal Article] Specific gene silencing in the pre-implantation stage mouse embryo by a siRNA expression vector system (2004)
  • Author(s): Haraguchi, S.et al.
  • Journal Title: Mol.Reprod.Dev 68 Pages: 17-24
  • NAID: 10012348758
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A novel apoptotic pathway induced by the drs tumor suppressor gene (2004)
  • Author(s): Tambe, Y.et al.
  • Journal Title: Oncogene 23 Pages: 2977-2987
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Loss of c-abl facilitates anchorage-independent growth of p53- and RB-deficient primary mouse embryonic fibroblasts (2004)
  • Author(s): Suzuki, J.et al.
  • Journal Title: Oncogene 23 Pages: 8527-8534
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Specific gene silencing in the pre-implantation stage mouse embryo by an siRNA expression vector system. (2004)
  • Author(s): Haraguchi, S., Saga, Y, Naito, K., Inoue, H., Seto, A.
  • Journal Title: Mol.Reprod.Dev. 68 Pages: 17-24
  • NAID: 10012348758
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel apoptotic pathway induced by the drs tumor suppressor gene. (2004)
  • Author(s): Tambe, Y., Isono, T..Haraguchi, S., Yoshioka-Yamashita, A, Yutsudo, M.,, Inoue.H.
  • Journal Title: Oncogene 23 Pages: 2977-2987
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Loss of c-abl facilitates anchorage-independent growth of p53-and RB-deficient primary mouse embryonic fibroblasts. (2004)
  • Author(s): Suzuki, J., Sukezane, T., Akagi, T., Georgescu, M.M., Ohtani, M., Inoue, H., Jat, P.S., Goff, S.P., Hanafusa, H., Shishido, Y.
  • Journal Title: Oncogene 23 Pages: 8527-8534
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel apoptotic pathway induced by the drs tumor suppressor gene. (2004)
  • Author(s): Tambe, Y. et al.
  • Journal Title: Oncogene 23 Pages: 2977-2987
• [Journal Article] Specific gene silencing in the pre-implantation stage mouse embryo by an siRNA expression vector system. (2004)
  • Author(s): Haraguchi, S et al.
  • Journal Title: Mol.Reprod.Dev. 68 Pages: 17-24
  • NAID: 10012348758
• [Journal Article] Loss of c-abl facilitates anchorage-independent growth of p53- and RB-deficient primary mouse embryonic fibroblast. (2004)
  • Author(s): Suzuki, J. et al.
  • Journal Title: Oncogene 23 Pages: 8527-8534
• [Journal Article] Pro-apoptotic ASY/Nogo-B protein associates with ASYIP (2003)
  • Author(s): Oi, B.et al.
  • Journal Title: J.Cell.Physiol. 196 Pages: 312-318
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Down-regulation of drs mRNA in human prostate carcinomas (2003)
  • Author(s): Kim, C.J.et al.
  • Journal Title: Human Pathology 34 Pages: 654-657
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of Epstein-Barr virus in thyroid carcinoma correlates with tumor progression (2003)
  • Author(s): Shimakage, M.et al.
  • Journal Title: Human Pathology 34 Pages: 1170-1177
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Conserved role of nanos proteins in germ cell development (2003)
  • Author(s): Tusda, M.et al.
  • Journal Title: Science 301 Pages: 1239-1241
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nanos 1 : a mouse nanos gene expressed in the central nerves system is dispensable for normal development (2003)
  • Author(s): Haraguchi, S.et al.
  • Journal Title: Mech.Dev. 120 Pages: 721-731
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pro-apoptotic ASY/Nogo-B protein associates with ASYIP. (2003)
  • Author(s): Qi, B., Qi, Y., Watari, A., Yoshioka, N., Inoue, H., Minemoto, Y., Yamashita, K., Sasagawa, T., Yutsudo, M.
  • Journal Title: J.Cell.Physiol. 196 Pages: 312-318
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Down-regulation of drs mRNA in human prostate carcinomas. (2003)
  • Author(s): Kim, C.J., Shimakage, M., Kushima, R., Mukaisho, K., Shinka, T., Okada, Y., Inoue.H.
  • Journal Title: Human Pathology 34 Pages: 654-657
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of Epstein-Barr virus in thyroid carcinoma correlates with tumor progression. (2003)
  • Author(s): Shimakage, M., Kawahara, K., Sasagawa, T., Inoue, H., Yutsudo, M., Yoshida, M., Yanoma, S.
  • Journal Title: Human Pathology 34 Pages: 1170-1177
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Conserved role of nanos proteins in germ cell development. (2003)
  • Author(s): Tsuda, M., Sasaoka, Y., Kiso, M., Abe, K., Haraguchi, S., Kobayashi, S., Saga, Y.
  • Journal Title: Science 301 Pages: 1239-1241
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] nanos1 : a mouse nanos gene expressed in the central nervous system is dispensable for normal development. (2003)
  • Author(s): Haraguchi, S., Tsuda, M., Kitajima, S., Sasaoka, Y, Nomura-Kitabayashid, A., Kurokawa, K., Saga, Y.
  • Journal Title: Mech.Dev. 120 Pages: 721-731
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rb1cc1 is critical for myoblast differentiation through Rb1 regulation
  • Author(s): Watanabe, R.et al.
  • Journal Title: Virchows Arch. 446(In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Periostin is down-regulated in high grade human bladder cancers and suppresses in vitro cell invasiveness and in vivo metastasis of cancer cells
  • Author(s): Kim, C.J.et al.
  • Journal Title: Int.J.Cancer (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Rb1cc1 is critical for myoblast differentiation through Rb1 regulation.
  • Author(s): Watanabe, R., Chano, T., Inoue, H., Isono, T., Koiwai, O., Okabe, H.
  • Journal Title: Virchows Arch. 446(in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Periostin is down-regulated in high grade human bladder cancers and suppresses in vitro cell invasiveness and in vivo metastasis of cancer cells.
  • Author(s): Kim, C.J., Yoshioka, N., Tambe, Y., Kushima, R., Okada, Y., Inoue, H.
  • Journal Title: Int.J.Cancer (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 生物薬科学実験講座6、細胞の増殖と成長因子、III 培養細胞の利用 「腫瘍ウイルスによる癌化に関する変異株」 (2005)
  • Author(s): 井上寛一(共著)
  • Publisher: 広川書店
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Qi, B.et al.: "Pro-apoptotic ASY/Nogo-B protein associates with ASYIP"J. Cell. Physiol. 196. 312-318 (2003)
• [Publications] Kim, C.J.et al.: "Down-regulation of drs mRNA in human prostate carcinomas"Human Pathology. 34. 654-657 (2003)
• [Publications] Shimakage, M. et al.: "Expression of Epstein-Barr virus in thyroid carcinoma correlates with tumor progression"Human Pathology. 34. 1170-1177 (2003)
• [Publications] Haraguchi, S. et al.: "nanos1 : a mouse nanos gene expressed in the central nervous system is dispensable for normal development"Mech. Dev.. 120. 721-731 (2003)
• [Publications] Tsuda, M. et al.: "Conserved role of nanos proteins in germ cell development"Science. 301. 1239-1241 (2003)
• [Publications] Tambe, Y. et al.: "A novel apoptotic pathway induced by the drs tumor suppressor gene"Oncogene. 23. 2977-2987 (2004)
• [Publications] Haraguchi, S. et al.: "Specific gene silencing in the pre-implantation stage mouse embryo by an si RNA expression vector system"Mol. Reprod. Dev.. in press.