Studies on the mechanism of Drs-mediated apoptosis and tumor suppression by gene-knockout mouse

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17590341
• 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 Shiga University of Medical Science, Department of Microbiology, Associate Professor, 医学部, 助教授 (30176440)
• Project Period (FY): 2005 – 2006
• Keywords: Tumor suppressor gene / Apoptosis / Knockout mouse / Drs / Autophagy / GADD34

Research Abstract

Drs protein associates with ASY/Nogo-B, an apoptosis-inducing protein in the endoplasmic reticulum, and sequentially activate caspases (-12,-9, and -3) to induce apoptosis in human cancer cells. Malignant tumors were generated in about 30% of the drs KO mice, indicating that drs contributes to the suppression of malignant tumor formation. In this study, we investigated the physiological roles of drs and the mechanism of tumor suppression by this gene by using drs KO mice and cells. The following results were obtained.
1.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-12,-9, and -3.
2.drs KO embryonic fibroblasts (MEF) also showed enhanced sensitivity to transformation by v-src oncogene.
3.Autophagy induced by low serum conditions was suppressed in drs KO MEF cells. Analyses with electron microscope and GFP-LC3 showed that drs is involved in the maturation process from autophagosomes to autolysosomes.
4.Drs associates with Rab24, which is involved in the autophagosome maturation, and colocalized with Rab24 on the autolysosomes during the late phase of autophagy induced by low serum.
5.Drs interacts with stress-inducible GADD34. Experiments with KO MEF cells, showed that drs and GADD34 are involved in survival in energy-depletion conditions and anti-viral defense via suppression of mTOR pathway.
These results idicate that drs is involved in the regulatuion of autophagy as well as apoptosis. Furthermore, drs plays a role in cell survival in stress conditions and anti-viral defense. By using KO mice and KO cells, we are going to clarify the physiological function of drs and the molecular mechanism of tumor suppression by drs.

Research Products

• [Journal Article] Tumor prone phenotype of mice deficient in a novel apoptosis-inducing gene, drs. (2007)
  • Author(s): Y.Tambe et al.
  • Journal Title: Carcinogenesis 28 Pages: 777-784
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] GADD34 inhibits mammalian target of rapamycin signaling via tuberous sclerosis complex and controls cell survival under bioenergetic stress. (2007)
  • Author(s): R.Watanabe et al.
  • Journal Title: Int. J. Mol. Med. 19 Pages: 475-483
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Down-regulation of drs mRNA is associated with the progression of adult T-cell leukemia/lymphoma. (2007)
  • Author(s): M.Shimakage et al.
  • Journal Title: Int. J. Oncol. 30 Pages: 1343-1348
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] GADD34 induces p21 expression and cellular senescence. (2007)
  • Author(s): K.Minami et al.
  • Journal Title: Oncol. Rep. 7 Pages: 1481-1485
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A novel tumor-related protein, C7orf24, identified by proteome differential display of bladder urothelial carcinoma. (2007)
  • Author(s): S.Kageyama et al.
  • Journal Title: Proteomics (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Tumor prone phenotype of mice deficient in a novel apoptosis-inducing gene, drs. (2007)
  • Author(s): Tambe, Y., Yoshioka-Yamashita, A., Mukaisho, K., Haraguchi, S., Chano, T., Isono, T., Kawai, T., Suzuki, Y., Kushima, R., Hattori, T., Goto, M., Yamada, S., Kiso, M., Saga, Y., Inoue, H.
  • Journal Title: Carcinogenesis 28 Pages: 777-784
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] GADD34 inhibits mammalian target of rapamycin signaling via tuberous sclerosis complex and controls cell survival under bioenergetic stress. (2007)
  • Author(s): Watanabe, R., Tambe, Y., Inoue, H., Isono, T., Haneda, M., Isobe, K., Kobayashi.T., Hino, 0., Okabe, H., Chano, T.
  • Journal Title: Int.J.Mol.Med. 19 Pages: 475-483
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Down-regulation of drs mRNA is associated with the progression of adult T-cell leukemia/lymphoma. (2007)
  • Author(s): Shimakage, M., Inoue, N., Oshima, K., Kawahara, K., Yamamoto, N., Oka, T., Tambe, Y., Yasui, K., Matsumoto, K., Yutsudo, M., Inoue H.
  • Journal Title: Int.J.Oncol. 30 Pages: 1343-1348
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] GADD34 induces p21 expression and cellular senescence. (2007)
  • Author(s): Minami, K., Inoue, H., Terashita, T., Kawakami, T., Watanabe, R., Haneda, M., Isobe, K., Okabe, H., Chano, T.
  • Journal Title: Oncol.Rep. 7 Pages: 1481- 1485
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Down-regulation of ASY/Nogo transcription associated with progression of adult T-cell leukemia/lymphoma. (2006)
  • Author(s): M.Shimakage et al.
  • Journal Title: Int. J. Cancer 119 Pages: 1648-1653
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neuromuscular abundance of RBICC1 contributes to the non-proliferating enlarged cell phenotype through both RB1 maintenance and TSC1 degradation. (2006)
  • Author(s): T.Chano et al.
  • Journal Title: Int. J. Mol. Med. 18 Pages: 425-432
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Down-regulation of ASY/Nogo Transcription associated with progression of adult T-cell leukemia/lymphoma. Int. (2006)
  • Author(s): Shimakage, M., Inoue, N., Oshima, K., Kawahara, K., Oka, T., Yasui, K., Matsumoto, K., Inoue H., Watari, A., Higashiyama, S., Yutsudo, M.
  • Journal Title: J.Cancer 119 Pages: 1648-1653
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neuromuscular abundance of RB1 CC1 contributes to the non-proliferating enlarged cell phenotype through both RB1 maintenance and TSC1 degradation. (2006)
  • Author(s): Chano, T, Saji, M., Inoue, H., Minami, K., Kobayashi, T., Hino, 0., Okabe, H.
  • Journal Title: Int.J.Mol.Med. 18 Pages: 425-432
  • 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. (2005)
  • Author(s): R.Watanabe et al.
  • Journal Title: Virchows Arch. 4462 Pages: 643-648
  • 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 vitro metastasis of cancer cells (2005)
  • Author(s): C.J.Kim et al.
  • Journal Title: Int. J. Cancer 117 Pages: 51-56
  • 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. (2005)
  • Author(s): Watanabe, R., Chano, T., Inoue H., Isono, T., Koiwai, 0., Okabe, H.
  • Journal Title: Virchows Arch 446 Pages: 643-648
  • 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. (2005)
  • Author(s): Kim, C.J., Yoshioka, N., Tambe, Y., Kushima, R., Okada, Y., Inoue, H.
  • Journal Title: Int.J.Cancer 117 Pages: 51-58
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel tumor-related protein, C7orf24, identified by proteome differential display of bladder urothelial carcinoma.
  • Author(s): Kageyama, S., Iwaki, H., Inoue, H., Isono, T., Yuasa, T., Nogawa, M., Maekawa, T., Ueda, M., Kajita, Y., Ogawa, 0., Toguchida, J., Yoshiki, T.
  • Journal Title: Proteomics (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)
  • Total Pages: 533-543
  • Publisher: 広川出版
  • Description: 「研究成果報告書概要(和文)」より