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Analysis of Thymidine phosphorylase- Uridine phosphorylase double knockout mice

Research Project

Project/Area Number 13670149
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionKagoshima University

Principal Investigator

HARAGUCHI Misako  Kagoshima University, Graduate School of Medical and Dental Science, Research Associated, 大学院・医歯学総合研究科, 助手 (10244229)

Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2002: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2001: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsThymidine phosphorylase / ウリジンホスホリラーゼ / ダブルノックアウトマウス / ミトコンドリア / MNGIE / 血管新生 / 白質脳症
Research Abstract

Thymidine phosphorylase (TP) is an enzyme involved in the reversible conversion of thymidine to thymine. In cancer patients and tumor-bearing animals, plasma TP level is elevated, and its expression in various solid tumors is higher than in the adjacent non-neoplastic tissues. Both TP itself and the degradation product of thymidine, 2-deoxy-D-ribose, had chemotactic and angiogenic activities, and the enzymatic activity of TP was required for its angiogenic activity. TP was expressed mainly at the invasive edges of tumors and TP expression was associated with the extent of invasion of gastric and colorectal carcinoma.
TP expression was also elevated in chronically inflamed tissues. TNF alpha and IFN gamma are reported to induce TP expression. To confirm the physiological role of TP, we generated mice deficient in TP gene (TPKO). TPKO mice showed an increased resistance to infection by Listeria monocytogenes. Splenic and hepatic bacterial loads 3 days after inoculation were decreased about 1 logs in TPKO. TPKO mice displays increase Interferon gamma level in plasma whereas less level of IL-10. The liver cells and spleen cells were obtained from infected mice, and cultured. The IL-10 levels in the conditioned media of the cells from TPKO mice were significantly less than those from wild-type mice. IL-10 is known to be a potent anti-inflammatory cytokine, and is suggested to reduce the function of tumor infiltrating lymphocytes and contributes the tumor growth. Therefore, we tried to test the role of TP in the escape of tumors from immune systems. Age and sex matched mice (wild-type and TP-/-) were injected i.p. with 1x10^6 of EL-4 cells. Two week after the challenge with EL-4 cells, the increase in volumes of ascites and the growth of EL-4 cells are significantly less in TPKO mice than in wild-type mice. Thus, TP may allow the escape of tumors from immune destruction and contribute the tumor growth.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Ikeda, -R;, Furukawa, -T;, Mitsuo, -R;, Noguchi, -T;, Kitazono, -M;, Okumura, -H;, Sumizawa, -T;, Haraguchi, -M;, Che, -X-F;, Uchimiya, -H;, Nakajima, -Y;, Ren, -X-Q;, Oiso, -S;, Inoue, -I;, Yamada, -K;, Akiyama,-S: "Thymidine phosphorylase inhibits apoptosis induced by cisplatin"Biochem-Biophys-Res-Commun.. 301 2. 358-363 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Haraguchi-M., Tsujimoto-H., Fukushima-M., Higuchi-I., Kuribayashi-H., Utsumi-H., Nakayama-A., Hashizume-Y., Hirato-J., Yoshida-H., Hara-H., Hamano-S., Kawaguchi-H., Furukawa-T., Miyazono-K., Ishikawa-F., Toyoshima-H., Kaname-T., Komatsu-M., Chen_Z.H., Gotanda-T., Tachiwada-T., Sumizawa-T., Miyadera-K., Osame-M., Yoshida-H., Noda-T., Yamada-Y., Akiyama-S.: "Targeted Deletion of both Thymidine Phosphorylase and Uridine Phosphorylase and consequent disorders in mice"Mol.Cell.Biol.. 22. 5212-5221 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uchimiya-H., Furukawa-T., Okamoto-M., Nakajima-Y., Matsushita-S., Ikeda-R., Gotanda-T., Haraguchi-M., Sumizawa-T., Ono-M., Kuwano-M., Kanzaki-T., Akiyama-S.: "Suppression of thymidine phosphorylase-mediated angiogenesis and tumor growth by 2-deoxy-L-ribose"Cancer Res.. 62. 2834-2839 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ikeda-R, Furukawa-T., Kitazono-M., Ishitsuka-K., Okumura-H., Tani-A., Sumizawa-T., Haraguchi-M., Komatsu-M., Uchimiya-H., Ren-X.Q., Motoya-T., Yamada-K., Akiyama-S: "Molecular basis for the inhibition of hypoxia-induced apoptosis by 2-deoxy-d-ribose"Biochem.Biophys.Res.Commun.. 291. 806-812 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ikeda,-R, Furukawa,-T., Mitsuo,-R, Noguchi,-T, Kitazono,-M, Okumura,-H, Sumizawa,-T, Haraguchi,-M, Che,-X-F, Uchimiya, -H, Nakajima,-Y, Ren,-X-Q, Oiso,-S, Inoue,-I, Yamada,-K, Akiyama,-S: "Thymidine phosphorylase inhibits apoptosis induced by cisplatin"Biochem-Biophys-Res-Commun. 301(2). 358-363 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Haraguchi-M., Tsujimoto-H., Fukushima-M., Higuchi-I., Kuribayashi-H., Utsumi-H., Nakayama-A., Hashizume-Y., Hirato-J., Yoshida-H., Hara-H., Hamano-S., Kawaguchi-H, Furukawa-T., Miyazono-K., Ishikawa-F., Toyoshima-H., Kaname-T., Komatsu-M., Chen-Z.H., Gotanda-T., Tachiwada-T., Sumizawa-T., Miyadera-K., Osame-M., Yoshida-H., Noda-T., Yamada,-Y. & Akiyama-S: "Targeted Deletion of both Thymidine Phosphorylase and Uridine Phosphorylase and consequent disorders in mice"Mol. Cell. Biol.. 22. 5212-5221 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uchimiya-H., Furukawa-T., Okamoto-M., Nakajima-Y., Matsushita-S., Ikeda-R., Gotanda-T., Haraguchi-M., Sumizawa-T., Ono-M., Kuwano-M., Kanzaki-T. & Akiyama-S: "Suppression of thymidine phosphorylase-mediated angiogenesis and tumor growth by 2-deoxy-L-ribose"Cancer Res.. 62. 2834-2839 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ikeda-R., Furukawa-T., Kitazono-M., Ishitsuka-K., Okumura-H., Tani-A., Sumizawa-T., Haraguchi-M., Komatsu-M., Uchimiya-H., Ren-X.Q., Motoya-T., Yamada-K. & Akiyama-S.: "Molecular basis for the inhibition of hypoxia-induced apoptosis by 2-deoxy-d-ribose"Biochem. Biophys. Res. Commun.. 291. 806-812 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ikeda-R: "Thymidine phosphorylase inhibits apoptosis induced by cisplatin"Biochem-Biophys-Res-Commun.. 301(2). 358-363 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ren, -X-Q: "A positively charged amino acid proximal to the C-terminus of TM17 of MRP1 is indispensable for GSH-dependent binding of substrates and for transport of LTC4"Biochemistry. 41(48). 14132-14140 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ikeda-R: "Molecular basis for the inhibition of hypoxia-induced apoptosis by 2-deoxy-d-ribose"Biochem. Biophys. Res. Commun.. 291. 806-812 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uchimiya-H: "Suppression of thymidine phosphorylase-mediated angiogenesis and tumor growth by 2-deoxy-L-ribose"Cancer Res.. 62. 2834-2839 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Haraguchi-M.: "Targeted Deletion of both Thymidine Phosphorylase and Uridine Phospshorylase and consequent disorders in mice"Mol. Cell. Biol.. 22. 5212-5221 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Furukawa-T.: "Thymidine Phosphorylase, a new molecular target for anti-cancer therapy"Current Topics in Biochemical Res.. 4. 89-95 (2001)

    • Related Report
      2002 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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