Gene expression network for tumor suppression

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 12219204
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: TANIGUCHI Tadatsugu The University of Tokyo, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (50133616)
• Co-Investigator(Kenkyū-buntansha): TAKAOKA Akinori The Univ. of Tokyo, Grad. Sch. of Med, Lecturer, 大学院医学系研究科, 講師 (30323611) ; HONDA Kenya The Univ. of Tokyo, Grad. Sch. of Med, Research Associate, 大学院医学系研究科, 助手 (60334231)
• Project Period (FY): 2000 – 2004
• Keywords: Interferon / IRF family / Noxa / p53 / dendritic cells / apoptosis / osteoclast / RANKL

Research Abstract

In the current study, we have made multifaceted approach to elucidate molecular mechanisms for oncogenesis, by analyzing not only the interrelationships between molecules which are involved in tumor suppression but also the gene expression network from both genetic and epigenetic aspects. Specifically, we found several important roles of "weak signal" by constitutively produced IFN-α/β in IFN-γ or IL-6-mediated cellular response as well as regulatory systems for cancer prevention. We also found a novel cross-talk mechanism between RANKL and IFN-γ, and clarified the regulatory role of the IFN system in osteoclast differentiation, which provided its putative therapeutic application to bone destruction by metastatic tumors. Development of autoimmune-like disease was observed in mice lacking IRF-2, which is an attenuator of IFN-a/β signaling. Further analyses revealed the role of IFN-α/β signaling in the regulation of CD8^+ T cell response. In these IRF-2-deficient mice, such hyperactivati on of IFN-α/β signaling affects normal differentiation of dendritic cells. IFN-α/β signaling is also found to be indispensable during DC maturation. Furthermore, it was demonstrated that another IRF-family member, IRF-7, is an essential transcriptional factor for the IFN induction in plasmacytoid DCs in response to unmethylated DNA (CpG), which is known to be a potent adjuvant for anti-tumor immunity. And we found a spaciotemporal regulation, by which plasmacytoid DCs are capable to produce IFN-α/β at high levels. On the other hand, IRF-5 is also found to be essentially involved in the CpG-induced production of proinflammatory cytokines. In addition, we identified novel p53 target genes, Noxa and Reprimo, which are involved in p53-mediated apoptosis or cell cycle arrest, respectively. Further study by generating Noxa-deficient mice revealed that Noxa may be a beneficial therapeutic target since it undergoes selective apoptosis in oncogene-expressing cells. Finally, we found an interrelationship between IFN-α/β signaling and p53-mediated response, which provided a novel aspect in terms of a linkage between tumor suppression and immunity.
Taken together, we believe that these research accomplishments contribute to some advance in understanding molecular mechanisms underlying tumor suppression, and provide a molecular basis for their clinical applications.

Research Products

• [Journal Article] Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. (2005)
  • Author(s): Takaoka, A., Yanai, H., Kondo, S., Duncan, G., Negishi, H., Mizutani, T., Kano, S., Honda, K., Ohba, Y., Mak, T.M., Taniguchi, T.
  • Journal Title: Nature Vol. 434, No 7030 Pages: 243-249
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IRF-7 is the master regulator of type-I interferon-dependent immune responses. (2005)
  • Author(s): Honda K., Yanai H., Negishi H., Asagiri M., Sato M., Mizutani T., Shimada N., Ohba Y., Takaoka A., Yoshida N., Taniguchi T.
  • Journal Title: Nature Vol 434, No. 7034 Pages: 772-777
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type I interferon induction (2005)
  • Author(s): Honda K., Ohba, Y., Yanai, H., Negishi, H., Mizutani, T., Takaoka, A., Taya C., Taniguchi, T.
  • Journal Title: Nature Vol 434 Pages: 1035-1040
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IRF-7 is the masterregulator of type-I interferon-dependent immune responses. (2005)
  • Author(s): Honda K., Yanai H., Negishi H., Asagiri M., Sato M., Mizutani T., Shimada N., Ohba Y., Takaoka A., Yoshida N., Taniguchi T.
  • Journal Title: Nature Vol 434, No. 7034 Pages: 772-777
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Spatiotemporal regulation of MyD88-IRF-7 signaling for robust type I interferon induction. (2005)
  • Author(s): Honda K., Ohba, Y., Yanai, H., Negishi, H., Mizutani, T., Takaoka, A., Taya, C., Taniguchi, T.
  • Journal Title: Nature Vol 434 Pages: 1035-1040
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. (2004)
  • Author(s): Koga, T., Inui, M., Inoue, K., Kim, S., Suematsu, A., Kobayashi, E., Iwata, T., Ohnishi, H., Matozaki, T., Kodama, T., Taniguchi, T., Takayanagi, H., Takai, T.
  • Journal Title: Nature vol. 428, no. 6984 Pages: 758-763
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Statl functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. (2003)
  • Author(s): Kim, S., Koga T., Isobe, M., Kern, B.E., Yokochi T., Karsenty, G., Taniguchi T., Takayanagi
  • Journal Title: Genes. Dev. 17 Pages: 1979-1991
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Integral role of Noxa in p53-mediated apoptotic response. (2003)
  • Author(s): Shibue, T., Takeda, K., Oda, E., Tanaka, H., Murasawa, H., Takaoka, A., Morishita, Y., Akira, S., Taniguchi, T., Tanaka, N.
  • Journal Title: Genes. Dev. 17 Pages: 2233-2238
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. (2003)
  • Author(s): Kim, S., Koga T., Isobe, M., Kern, B.E., Yokochi T., Karsenty, G., Taniguchi T., Takayanagi, H.
  • Journal Title: Genes. Dev. 17 Pages: 1979-1991
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β (2002)
  • Author(s): Takayanagi, H., Kim, S., Matsuo, K., Suzuki, H., Suzuki, T., Sato, K., Yokochi, T., Oda, H., Nakamura, K., Ida, N., Wagner, E.F., Taniguchi
  • Journal Title: Nature 416 Pages: 744-749
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β (2002)
  • Author(s): Takayanagi, H., Kim, S., Matsuo, K., Suzuki, H., Suzuki, T., Sato, K., Yokochi, T., Oda, H., Nakamura, K., Ida, N., Wagner, E.F., Taniguchi, T.
  • Journal Title: Nature 416 Pages: 744-749
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Noxa, a BH3-only member of the Bcl-2 family, and candidate mediator of p53-induced apoptosis. (2000)
  • Author(s): Oda, E., Ohki, R., Murasawa, H., Nemoto, J., Shibue, T., Yamashita, T., Tokino, T., Taniguchi, T., Tanaka, N.
  • Journal Title: Science 288 Pages: 1053-1058
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Crosstalk between interferon-γand-α/βsignaling components at caveolar membrane domain. (2000)
  • Author(s): Takaoka.A., Mitani, Y., Suemori, H., Sato, S., Yokochi, T., Noguchi, S., Tanaka, N., Taniguchi, T.
  • Journal Title: Science 288 Pages: 2357-2360
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] CD8+ T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-α/βsignaling. (2000)
  • Author(s): Hida, S., Ogasawara, K., Sato, K., Abe, M., Takayanagi, H., Yokochi, T., Sato, T., Hirose, S., Shirai, T., Taki, S., Taniguchi, T.
  • Journal Title: Immunity 13 Pages: 643-655
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. (2000)
  • Author(s): Takayanagi, H., Ogasawara, K., Hida, S., Chiba, T., Murata, S., Sato, K., Takaoka, A., Yokochi, T., Oda, H., Tanaka, K., Nakamura, k., Taniguchi, T.
  • Journal Title: Nature 408 Pages: 600-605
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Crosstalk between interferon-γ and-α/β signaling components at caveolar membrane domain. (2000)
  • Author(s): Takaoka, A., Mitani, Y., Suemori, H., Sato, S., Yokochi, T., Noguchi, S., Tanaka, N., Taniguchi, T.
  • Journal Title: Science 288 Pages: 2357-2360
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CD8+ T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-α/β signaling. (2000)
  • Author(s): Hida, S., Ogasawara, K., Sato, K., Abe, M., Takayanagi, H., Yokochi, T., Sato, T., Hirose, S., Shirai, T., Taki, S., Tanicuhi, T.
  • Journal Title: Immunity 13 Pages: 643-655
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] T-cell-mediated regulation of osteoclastogenesis by signaling cross-talk between RANKL and IFN-γ. (2000)
  • Author(s): Takayanagi, H., Ogasawara, K., Hida, S., Chiba, T., Murata, S., Sato, K., Takaoka, A., Yokochi, T., Oda, H., Tanaka, K., Nakamura, k., Taniguchi, T.
  • Journal Title: Nature 408 Pages: 600-605
  • Description: 「研究成果報告書概要(欧文)」より