Chemical genetics on protein acetylation, a key reaction regulating biological functions

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 15208010
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied biochemistry
• Research Institution: RIKEN
• Principal Investigator: YOSHIDA Minoru RIKEN, Chemical Genetics Laboratory, Director (80191617)
• Co-Investigator(Kenkyū-buntansha): YASHIRODA Yoko RIKEN, Chemical Genetics Laboratory, Researcher (60360658) ; YOSHIDA Yukiko Tokyo Metropolitan Organization for Medical Research, 東京都臨床医学総合研究所, Researcher (90271543) ; KAMEMURA Kazuo Nagahama Institute of Bio-Science & Technology, Department of Bio-Science, Lecturer (00399437)
• Project Period (FY): 2003 – 2005
• Keywords: HDAC / Trichostatin A / transcription / Hsp90 / SIRT / CBP

Research Abstract

Among the histone deacetylase (HDAC) enzymes, molecular functions of HDAC4, which localizes in the HDAC4/Bach2 body, and HDAC6, which localizes in the cytoplasm and deacetylates tubulin, were studied. As a result, we found that HDAC4, as well as Bach2, relocalized to the nucleus in response to oxidative stress, and accumulated in the punctate structures that surround the PML bodies. The transcription labeling experiments revealed that the nuclear regions in and around the PML bodies surrounded by HDAC4/Bach2 were transcriptionally inactivated. In the case of HDAC6, we showed that HDAC6 expression repressed the endocytosis of both EGF receptor and transferrin receptor. In the lung cancer cells stably expressing siRNA for the knock down of HDAC6, EGF-induced EGF receptor endocytosis was greatly enhanced thereby down-regulating the level of EGF receptor. However, these cells can grow by compensating the EGF signaling by overexpression of the downstream ERK. These results indicate that HDAC6 regulates the signaling pathways of receptor tyrosine kinases by controlling endocytosis. Furthermore, we searched for novel acetylated proteins using specific HDAC inhibitors, and identified several proteins including Hsp90, SV40 large T-antigen, and poly(A) polymerase (PAP). We also identified more than ten proteins that are acetylated in the fission yeast cells. The functional analysis demonstrated that acetylation caused a decrease in the activity of Hsp90, destabilized the SV40 large T-antigen, and suppressed the nuclear import of PAP. These findings imply that acetylation occurs on a wide variety of cellular proteins and profoundly regulates the protein function.

Research Products

• [Journal Article] Regulation of SV40 large T antigen stability by reversible acetylation (2006)
  • Author(s): Shimazu, T. et al.
  • Journal Title: Oncogene (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of SV40 large T antigen stability by reversible acetylation. (2006)
  • Author(s): Shimazu, T., Komatsu, Y., Nakayama, K.I., Fukazawa, H., Horinouchi, S., Yoshida, M.
  • Journal Title: Oncogene (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor (2005)
  • Author(s): Kovacs, J.J. et al.
  • Journal Title: Molecular Cell 18・5 Pages: 601-607
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Design and synthesis of phthalimide-type histone deacetylase inhaibitors (2005)
  • Author(s): Shinji, C. et al.
  • Journal Title: Bioorg.Med.Chem.Lett. 15 Pages: 4427-4431
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer (2005)
  • Author(s): Saji S.et al.
  • Journal Title: Oncogene 24・28 Pages: 4531-4539
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Proteomic analysis of organ-specific post-translational lysine-acetylation and methylation in mice by use of anti-acetyllysine and methyllysine mouse monoclonal antibodies (2005)
  • Author(s): Iwabata, H. et al.
  • Journal Title: Proteomics 5・18 Pages: 4653-4664
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] HIV-Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses (2005)
  • Author(s): Col, E.et al.
  • Journal Title: The EMBO Journal 24・14 Pages: 2634-2645
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. (2005)
  • Author(s): Kovacs, J.J., Murphy, P.J.M., Gaillard, S., Zhao, X., Wu, J.-T., Nicchitta, C.V., Yoshida, M., Toft, D.O., Pratt, W.B., Yao, T.-P.
  • Journal Title: Mol.Cell 18 Pages: 601-607
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Design and synthesis of phthalimide-typehistonedeacetylase inhibitors. (2005)
  • Author(s): Shinji, C., Nakamura, T., Maeda, S., Yoshida, M., Hashimoto, Y., Miyachi, H.
  • Journal Title: Bioorg Med Chem Lett. 15 Pages: 4427-4431
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. (2005)
  • Author(s): Saji, S., Kawakami, M., Hayashi, S.I., Yoshida, N., Hirose, M., Horiguchi, S.I., Itoh, A., Funata, N., Schreiber, S.L., Yoshida, M., Toi, M.
  • Journal Title: Oncogene 24 Pages: 4531-4539
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Proteomic analysis of organ-specific post-translational lysine-acetylation and -methylation in mice by use of anti-acetyllysine and-methyllysine mouse monoclonal antibodies. (2005)
  • Author(s): Iwabata, H., Yoshida, M., Komatsu, Y.
  • Journal Title: Proteomics 5 Pages: 4653-4664
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] HIV-Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses. (2005)
  • Author(s): Col, E., Caron, C., Chable-Bessia, C., Legube, G., Gazzeri, S., Komatsu, Y., Yoshida, M., Benkirane, M., Trouche, D., Khochbin, S.
  • Journal Title: EMBO J. 24 Pages: 2634-2645
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Repression of PML nuclear body-associated transcription by oxidative stress-activated Bach2 (2004)
  • Author(s): Tashiro, S. et al.
  • Journal Title: Mol.Cell.Biol. 24・8 Pages: 3473-3484
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Subtype selective substrates for histone deacetylases (2004)
  • Author(s): Heltweg, b. et al.
  • Journal Title: J.Med.Chem. 47 Pages: 5235-5243
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Chlamydocin-hydroxamic acid analogues as histone deacetylase inhibitors (2004)
  • Author(s): Nishino, N. et al.
  • Journal Title: Bioorg.Med.Chem. 12 Pages: 5777-5784
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis and histone deacetylase inhibbitory activity of cyclic tetrapeptides containing a retrohydroxamate as zine ligand (2004)
  • Author(s): Nishino, N. et al.
  • Journal Title: Bioorg.Med.Chem.Lett. 14 Pages: 2427-2431
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Novel histone deacetylase inhibitors : cyclic tetrapeptide with trifluoromethyl and pentafluoroethy ketones (2004)
  • Author(s): Jose, B. et al.
  • Journal Title: Bioorg.Med.Chem.Lett. 14 Pages: 5343-5346
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Toward an HDAC6 inhibitor : synthesis and conformational analysis of cyclic hexapeptide hydroxamic acid designed from a-tubulin sequence (2004)
  • Author(s): Jose, B. et al.
  • Journal Title: Bioorg.Med.Chem. 12 Pages: 1351-1356
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Repression of PML nuclear body-associated transcription by oxidative stress-activated Bach2. (2004)
  • Author(s): Satoshi, T., Akihiko, M., Keiji T., Haaruka, T., Hiroshi S., Hideto, H., Minoru, Y., Joachim W., Kazuhiko I.
  • Journal Title: Mol.Cell.Biol. 24 Pages: 3473-3484
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Subtype selective substrates for histone deacetylases. (2004)
  • Author(s): Heltweg, B., Dequiedt, F., Marshall, B.L., Brauch, C., Yoshida, M., Nishino, N., Verdin, E., Jung, M.
  • Journal Title: J.Med.Chem. 47 Pages: 5235-5243
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chlamydocin-hydroxamic acid analogues as histone deacetylase inhibitors. (2004)
  • Author(s): Nishino, N., Jose, B., Shinta, R., Kato, T., Komatsu, Y., Yoshida, M.
  • Journal Title: Bioorg.Med.Chem. 12 Pages: 5777-5784
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis and histone deacetylase inhibitory activity of cyclic tetrapeptides containing a retrohydroxamate as zinc ligand. (2004)
  • Author(s): Nishino, N., Yoshikawa, D., Watanabe, L.A., Kato, T., Jose, B., Komatsu, Y., Sumida, Y., Yoshida, M.
  • Journal Title: Bioorg.Med.Chem.Lett. 14 Pages: 2427-2431
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Novel histone deacetylase inhibitors : cyclic tetrapeptide with trifluoromethyl and pentafluoroethyl ketones. (2004)
  • Author(s): Jose, B., Oniki, Y., Kato, T., Nishino, N., Sumida, Y., Yoshida, M.
  • Journal Title: Bioorg.Med.Chem.Lett. 14 Pages: 5343-5346
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Toward an HDAC6 inhibitor : synthesis and conformational analysis of cyclic hexapeptide hydroxamic acid designed from a-tubulin sequence. (2004)
  • Author(s): Jose, B., Okamura, S., Kato, T., Nishino, N., Sumida, Y., Yoshida, M.
  • Journal Title: Bioorg.Med.Chem. 12 Pages: 1351-1356
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Protein deacetylases : enzymes with functional diversity as novel therapeutic targets (2003)
  • Author(s): Yoshida, M. et al.
  • Journal Title: Prog.Cell Cycle Res. 5 Pages: 269-278
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] From discovery to the coming generation of histone deacetylase inhibitors (2003)
  • Author(s): Yoshida, M. et al.
  • Journal Title: Curr.Med.Chem. 10 Pages: 2351-2358
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Four different clones of mouse anti-acetyllysine monoclonal antibodies having different recognition properties share a common immunoglobulin framework structure (2003)
  • Author(s): Komatsu, Y. et al.
  • Journal Title: J.Immunol.Methods 272 Pages: 161-175
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cyclic tetrapeptides bearing sulfhydoryl group potently inhibit histone deacetylases (2003)
  • Author(s): Nishino, N. et al.
  • Journal Title: Org.Lett. 5・26 Pages: 5079-5082
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Protein deacetylases : enzymes with functional diversity as novel therapeutic targets. (2003)
  • Author(s): Yoshida, M., Shimazu, T., Matsuyama, A.
  • Journal Title: Prog.Cell Cycle Res. 5 Pages: 269-278
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] From discovery to the coming generation of histone deacetylase inhibitors. (2003)
  • Author(s): Yoshida, M., Matsuyama, A., Komatsu, Y., Nishino, N.
  • Journal Title: Curr.Med.Chem. 10 Pages: 2351-2358
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Four different clones of mouse anti-acetyllysine monoclonal antibodies having different recognition properties share a common immunoglobulin framework structure. (2003)
  • Author(s): Komatsu, Y., Yukutake, Y., Yoshida, M.
  • Journal Title: J.Immunol.Methods 272 Pages: 161-175
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cyclic tetrapeptides bearing sulfhydoryl group potently inhibit histone deacetylases. (2003)
  • Author(s): Nishino, N., Jose, B., Okamura, S., Ebisusaki, S., Kato, T., Sumida, Y., Yoshida, M.
  • Journal Title: Org.Lett. 5 Pages: 5079-5082
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Histone Deacetylases (2006)
  • Author(s): Akihiro Ito, Norikazu Nishino, Minoru Yoshida
  • Total Pages: 27
  • Publisher: The Humana Press Inc.
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 糸状菌の分化抑制剤 (2006)
  • Inventor(s): 鎌倉高志, 西野憲和, 吉田稔
  • Industrial Property Rights Holder: 東京理科大学, 九州工業大学, 理化学研究所
  • Industrial Property Number: 特願2006-058011
  • Filing Date: 2006-03-03
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] HDAC阻害活性を有する新規置換ヒドロキサム酸誘導体 (2005)
  • Inventor(s): 宮地弘幸, 橋本祐一, 進士千尋, 吉田稔
  • Industrial Property Rights Holder: 東京大学理化学研究所
  • Industrial Property Number: 特願2005-267767
  • Filing Date: 2005-09-15
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] ヒストン脱アセチル化酵素阻害剤およびその製造方法 (2003)
  • Inventor(s): 吉田稔, 西野憲和
  • Industrial Property Rights Holder: 理化学研究所, 株式会社先端科学技術インキュベーションセンター
  • Industrial Property Number: 特願2003-177298
  • Filing Date: 2003-06-20
  • Description: 「研究成果報告書概要(和文)」より