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2001 Fiscal Year Final Research Report Summary

Development of specific prevention against people with high susceptibility for cancer and general carcinogenesis

Research Project

Project/Area Number 10470097
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Hygiene
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

SAKAI Toshiyuki  Kyoto Prefectural University of Medicine, Department of Preventive Medicine, Professor, 医学部, 教授 (20186993)

Co-Investigator(Kenkyū-buntansha) YOSHIDA Tatsushi  Kyoto Prefectural University of Medicine, Department of Preventive Medicine, Assistant Professor, 医学部, 助手 (80315936)
MATSUZAKI Youichirou  Kyoto Prefectural University of Medicine, Department of Preventive Medicine, Assistant Professor, 医学部, 助手 (70282522)
SOWA Yoshihirio  Kyoto Prefectural University of Medicine, Department of Preventive Medicine, Lecturer, 医学部, 講師 (70315935)
Project Period (FY) 1998 – 2001
Keywordsp21 / WAF1 / gadd45 / cancer / p53 / prevention / promoter / p27 / histone deacetylase inhibitor
Research Abstract

1. p27 is a crucial tumor-suppressor gene. Vitamin D3 (VD3) activated p27 via promoter region and repressed cell growth. VD3 stimulated transcription of the p27 by a novel mechanism involving Sp1 and NF-Y, but not the VD3 receptor. These results indicate that we could develop a new drug without side effect such as hypercalcemia mediated by the VD3 receptor.
2. Butyrate, a dietay fiber metabolite, activated p21/WAF1 and acted as histone deacetylase (HDAC) inhibitor. We previously reported that butyrate activated p21/WAF1 by Sp1 and Sp3 through Sp1 site of the promoter. Moreover, butyrate activated gadd45 causing cell-cycle arrest and DNA repair. This activation is mediated through Oct-1 box and CCAAT box. p21/WAF1 and gadd45 are regulated by p53. p53 is critical factor in Li-Fraumeni syndrome and is inactivated in a half of malignancies. HDAC inhibitors which activate p21/WAF1 and gadd45 mght be preventive against patient of Li-Fraumeni syndrome or common cancer.
3. p16 as well as p53 is a gene inactivated in a half of malignancies. The promoter regions of p16 gene, p15-family genes (p15, p18 and p19) and p53-regulated genes (BAX, DR5, Sian-1 and PUMA) were cloned. We screened drugs activating these genes via these promoter regions and found intersting regulators. These regulators may become novel drugs for prevention of specific cancer.

  • Research Products

    (50 results)

All Other

All Publications (50 results)

  • [Publications] Maeda, A et al.: "The characterization of the human Siah-1 promoter"FEBS Letters. 512. 223-226 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Onishi, K et al.: "SMRT as a T3SF-biriding protein"Int. J. Oncol.. 18. 985-989 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshida, T et al.: "Promoter structure and transcription initiation sites of the human Death Receptor5/TRAIL-R2 gene"FEBS Letters. 507. 381-385 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matikainen, T et al.: "Aromatic hydrocarbon receptor-driven Bax gene expression is requirede for premature ovarian failure caused by biohazardous environmental chemicals"Nature Genet.. 28. 355-360 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takahashi, S et al.: "Involvement o the Oct-1 regulatory element of the gadd45 promoter in the p53-independent response to ultraviolet irradiation"Cancer Research. 61. 1187-1195 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kanemitsu, N et al.: "Correlation between induction of the mac25 gene and anti-protiteative efects of 1,25(OH)2-D3 on breast cancer and leukemic cells"Int. J. Mol. Med.. 7. 515-520 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sowa, Y et al.: "Butyrate as a model for "gene-regulating chemoprevention and chemotherapy.""Biofactors. 12. 283-287 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sasaki, K et al.: "Expressionand role of p27(kipl) in neuronal differeritiation of erubryonal carcinoma cells"Brain Res. Mol. Brain Res.. 77. 209-221 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Huang, L et al.: "Activation of the p21/WAF1/CIP1 promoter independent of p53 by the histone deacetylase inhibitor suberoylarilide hydroxamic acid (SAHA) through the Sp1 sites"Oncogene. 19. 5712-5719 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kanemitsu, N et al.: "Characterization of the promoter of the murine mac25 gene"Biochemical Biophysical and Research Communications. 279. 251-257 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Evdokiou, A et al.: "Identification of a novel calcitonin-response element in the promoter of the human p21WAF1/CIP1 gene"Journal of Molecular Endocrinology. 25. 195-206 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ueno, M et al.: "Thioredoxin-dependent redox regulation of p53-mediated p21 activation"The Journal of Biological Chemistry. 274. 35809-35815 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Inoue, T et al.: "Sp1 and NF-Y synergistically mediate the effect of vitamin D3 in the p27Kip1 gene promoter that lacks vitamin D response elements"The Journal of Biological Chemistry. 274. 32309-32317 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Igata, E et al.: "Molecular cloning and functional analysis of the murine bax gene promoter"Gene. 238. 407-415 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ding, Y et al.: "Molecular cloning and functional characterization of the upstream promoter region of the human p73 gene"DNA Research. 6. 347-351 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ding, Y et al.: "Growth inhibition of A549 human lung adenocarciflorna cells by L-canavanine is associated with p21/WAF1 induction"Japanese Journal of Cancer Research. 90. 69-74 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kamiyama, J et al.: "The ubioultous transcriotion factor NF-Y positively requlates the trariscriotion of human p27Kip1 through a CCAAT box located in the 5-upstream region of the p27K1 gene"FEBS Letters. 455. 281-285 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sowa, Y et al.: "Sp3, but not Sp1, mediates the transcriptional activation of the p21/WAF1/Cip1 gene promoter by histone deacetylase inhibitor"Cancer Research. 59. 4266-4270 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fujita, T et al.: "Low frequency at oncogenic mutations in me core promoter region of the RB1 gene"Human Mutation. 13. 410-411 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tamura, Y et al.: "Differential activity of a variant form of the human ld-i protein generated by alternative splicing"FEBS Letters. 436. 169-173 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kato, D et al.: "Features of replicative senescence induced by direct addition of antennapedia-p16^<INK4A> fusion protein to human diploid fibroblasts"FEBS Letters. 27. 203-208 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsumoto, T et al.: "Cell cycle-dependent modulation of promoter activities of RB and WAF1/Cip1 genes"Japanese Journal of Cancer Research. 89. 626-633 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsumoto, T et al.: "p53-independent induction of WAF1/Cip1 is correlated with osteoblastic differentiation by vitamin D_3"Cancer Letters. 129. 61-68 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ohtani-Fujita, N et al.: "p53 independent activation of the gadd45 promoter by Δ^<12> prostaglandin J_2"Biochemical and Biophysical Research Communications. 251. 648-652 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Bai, F et al.: "Promoter activation and following induction of the p21/WAF1 gene by flavone is involved in G1 phase arrest in A549 lung adenocarcinoma cells"FEBS Letters. 437. 61-64 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Bai F., Matsui T., Ohtani-Fujita N., Matsukawa Y., Ding Y., and Sakai T.: "Promoter activation and following induction of the p21/WAF1 gene by flavone is involved in G1 phase arrest in A549 lung adenocarcinoma cells"FEBS Letters. 437. 61-64 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ohtani-Fujita N., Minami S., Mimaki S., Dao S. and Sakai T.: "p53 independent activation of the gadd45 promoter by Δ12 prostaglandin J_2"Biochemical and Biophysical Research Communications. 251. 648-652 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsumoto T., Sowa Y., Ohtani-Fujita N., Tamaki T., Takenaka T., Kuribayashi K. and Sakai T.: "p53-independent induction of WAF1/Cip1 is correlated with osteoblastic differentiation by vitamin D_3"Cancer Letters. 129. 61-68 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsumoto T., Ohtani-Fuhita N., Sowa Y., Bai F., Nikaido T., Tamaki T. and Sakai T.: "Cell cycle-dependent modulation of promoter acitvities of RB and WAF1/Cip1 genes"Japanese Journal of Cancer Research. 89. 626-633 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kato D., Miyazawa K., Ruas M., Starborg M., Wada I., Oka T., Sakai T., Peters G. and Hara E.: "Features of replicative senescence induced by direct addition of antennapedia-p16^<ink4a> fusion protein to human diploid fibroblasts"FEBS Letters. 27. 203-208 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tamura Y., Sugimoto M., Ohnishi K., Sakai T. and Hara E.: "Differential activity of a variant form of the human Id-1 protein generated by alternative splicing"FEBS Letters. 436. 169-73 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sowa Y., Orita T., Minamikawa-Hiranabe S., Mizuno T., Nomura H. and Sakai T.: "Sp3, but not Sp1, mediates the transcriptional activation of the p21/WAF1/Cip1 gene promoter by histone deacetylase inhibitor"Cancer Research. 59. 4266-70 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kamiyama J., Inoue T., Ohtani-Fijita N., Minami S., Yamagishi H. and Sakai T.: "The ubiquitous transcription factor NF-Y positively regulates the transcription of human p27^<Kip1> through a CCAAT box located in the 5-upstream region of the p27^<Kip1> gene"FEBS Letters. 455. 281-5 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fujita T., Ohtani-Fijita N., Sakai T., Rapaport J. M., Dryja T. P., Kato M. V., Ishizaki K., Sasaki M. S. Hotta Y., Maeda K., Kinoshita S., Ohnishi Y. and Minoda K.: "Low frequency of oncogenic mutations in the core promoter region of the RB1 gene"Human Mutation. 13. 410-1 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ding Y., Matsukawa Y., OhtaniFujita N., Kato D., Dao S., Fujii T., Naito Y., Yoshikawa T., Sakai T. and Rosental G. A.: "Growth inhibition of A549 human lung adenocarcinoma cells by L-canavanine is associated with p21/WAF1 induction"Japanese Journal of Cancer Research. 90. 69-74 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ding Y., Inoue T., Kamiyama J., Tamura Y., Ohtani-Fujita N., Igata E., Sakai T.: "Molecular cloning and functional characterization of the upstream promoter region of the human p73 gene"DNA Research. 6. 347-351 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Igata E., Inoue T., Ohtani-Fujita N., Sowa Y., Tsujimoto Y. and Sakai T.: "Molecular cloning and functional analysis of the murine bax gene promoter"Gene. 237. 407-415 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Inoue T., Kamiyama J. and Sakai T.: "Sp1 and NF-Y synergistically mediate the effect of vitamin D_3 in the p27^<Iip1> gene promoter that lacks vitamin D response elements"The Journal of Biological Chemistry. 274. 32309-32317 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ueno M., Masutani H., Arai R. J., Yamauchi A., Hirota K., Sakai t., Inamoto T.: "Thioredoxin-dependent redox regulation of p53-mediated p21 activation"The Journal of Biological Chemistry. 274. 35809-35815 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Evdokiou A., Raggatt L. -J., Sakai T. and Findlay D. M.: "Identification of a novel calcitonin-response element in the promoter of the human p21^<WAF1/CIP1> gene. Journal of Molecular Endocrinology, 25 : 195-206, 2000"Journal of Molecular Endocrinology. 25. 195-206 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kanemitsu N., Kato M. V., Miki T., Komatsu S., Okazaki Y., Hayashizaki Y. and Sakai T.: "Characterization of the promoter of the murine mac25 gene"Biochemical and Biophysical Research Coomunications. 279. 251-257 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Huang L., Sowa Y., Sakai T. and Pardee A. B.: "Activation of the p21/WAF1/CIP1 promoter independent of p53 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) through the Sp1 sites"Oncogene. 19. 5712-5719 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sasaki K., Tamura S., Tachibana H., Sugita M., Gao Y., Furuyama J., Kakishita E., Sakai T., Tamaoki T. and Hashimoto-Tamaoki T.: "Expression and role of p27 (kip1) in neuronal differentiation of embryonal carcinoma cells"Brain Res. Mol. Brain Res.. 77. 209-21 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sowa Y., Sakai T.: "Butyrate as a model for "gene-regulating chemoprevention and chemotherapy.""Biofactors. 12. 283-287 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshida T., Maeda A., Tani N., Sakai T.: "Promoter structure and transcription initiation sites of the human Death Receptor 5/TRAIL-R2 gene"FEBS Letters. 507. 381-5 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matikainen T., Perez GI., Jurisicova A., Pru JK., Schlezinger JJ., Ryu HY., Laine J., Sakai T., Korsmeyer SJ., Casper RF., Sherr DH., Tilly JL.: "Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovaran failure caused by biohazardous environmental chemicals"Nature Genet. 28. 355-360 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takahashi S., Saito S., Ohtani N., Sakai T.: "Involovement of the Oct-1 regulatory element of the gadd45 promoter in the p53-independent response to ultraviolet irradiation"Cancer Research. 61. 1187-1195 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kanemitsu N., Kato M. V., Bai F., Miki T., Inoue T., Sakai T.: "Correlation between induction of the mac25 gene and anti-proliferative effects of 1, 25 (OH)2-D3 on breast cancer and leukemic cells"Int. J. Mol. Med.. 7. 515-20 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Onishi K., Kato M. V., Bai F., Sakai T.: "SMRT as a T3SF-binding protein"Int. J. Oncol.. 18. 985-989 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Maeda A., Yoshida T., Kusuzaki K., Sakai T.: "The characterization of the human Siah-1 promoter"FEBS Letters. 512. 223-226 (2002)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2003-09-17  

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