Regulation of inflammatory response via ubiquitin-dependent degradation by Fbw7

• Project/Area Number: 15K06994
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: KITAGAWA KYOKO 浜松医科大学, 医学部, 助教 (20299605)
• Research Collaborator: Kitagawa Masatoshi
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: Fbw7 / 炎症 / c-Myb / 血球細胞 / CXCL13 / GATA2 / 造血幹細胞

Outline of Final Research Achievements

Both c-Myb and GATA3 are the targets of Fbw7-mediated ubiquitylation. A knock-in strategy to express Fbw7-mediated degradation resistant mutant of c-Myb in mice was performed. In lung of some homozygous knock-in mice, lymphocytic infiltration which was mainly comprised of B cells was observed, and some cells in the region were expressed c-Myb.
CXCL13 which expresses in accordance with an inflammation is a chemotactic factor for B cell to a damage site, c-Myb responsive sequences are included in its promoter region. The transcriptional activity of c-Myb on the CXCL13 promoter region was confirmed by luciferase assay, indeed, GATA3 which is also a target of Fbw7 produced synergistic effect with c-Myb. It is suggested that Fbw7 associates with the regulation of CXCL13 expression level by quantative regulation of its targets.

Academic Significance and Societal Importance of the Research Achievements

Fbw7の欠損はc-MybおよびGATA3の分解阻害をもたらし、血球系細胞の分化増殖阻害を発生させる可能性があることは過去に報告したが、本研究によって炎症発生に伴って免疫細胞がCXCL13を産生する際に、Fbw7による量的調節を受けたc-MybとGATA3が相乗的な発現促進作用を持つ可能性が示唆された。両因子の相乗作用はIL-13発現においても過去の報告で認められており、複数の炎症性サイトカインの発現調節にFbw7がこれら転写因子の量的調節を介して関与していると考えられる。このことからFbw7活性調節が新規抗炎症薬での分子標的の候補になることが期待される。

Research Products

• [Journal Article] Long noncoding RNA ELIT-1 acts as a Smad3 cofactor to facilitate TGF-β/Smad signaling and promote epithelial-mesenchymal transition. (2019)
  • Author(s): Sakai, S., Ohhata, T., Kitagawa, K., Uchida, C., Aoshima, T., Niida, H., Suzuki, T., Inoue, Y., Miyazawa, K. and Kitagawa, M.
  • Journal Title: Cancer Res. Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis. (2018)
  • Author(s): Mikamo M, Kitagawa K, Sakai S, Uchida C, Ohhata T, Nishimoto K7,8, Niida H9, Suzuki S, Nakayama KI, Inui N, Suda T, Kitagawa M
  • Journal Title: Int J Mol Sci. Volume: 19 (2) Issue: 2 Pages: 474-474
  • DOI: 10.3390/ijms19020474
  • Peer Reviewed / Open Access
• [Journal Article] Tenascin C in colorectal cancer stroma is a predictive marker for liver metastasis and is a potent target of miR-198 as identified by microRNA analysis. (2017)
  • Author(s): Murakami, T., Kikuchi, H., Ishimatsu, H., Iino, I., Hirotsu, A., Matsumoto, T., Ozaki, Y., Kawabata, T., Hiramatsu, Y., Ohta, M., Kamiya, K., Fukushima, M., Baba, S., Kitagawa, K., Kitagawa, M. and Konno H
  • Journal Title: Br J Cancer. Volume: 117(9) Issue: 9 Pages: 1360-1370
  • DOI: 10.1038/bjc.2017.291
  • Peer Reviewed / Open Access
• [Journal Article] Homeobox Transcription Factor NKX2-1 Promotes Cyclin D1 Transcription in Lung Adenocarcinomas. (2017)
  • Author(s): Harada M, Sakai S, Ohhata T, Kitagawa K, Mikamo M, Nishimoto K, Uchida C, Niida H, Kotake Y, Sugimura H, Suda T, Kitagawa M.
  • Journal Title: Mol. Cancer Res. Volume: 15(10) Pages: 1388-1397
  • Peer Reviewed
• [Journal Article] Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair (2017)
  • Author(s): Niida, H., Matsunuma, R., Horiguchi, R., Uchida, C., Nakazawa, Y., Motegi, A., Nishimoto, K., Sakai, S., Ohhata, T., Kitagawa, K., Moriwaki, S., Nishitani, H., Ui, A., Ogi, T. and Kitagawa, M.
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 16102-16102
  • DOI: 10.1038/ncomms16102
  • Peer Reviewed / Open Access
• [Journal Article] Roles of defective ALDH2 polymorphism on liver protection and cancer development. (2016)
  • Author(s): Matsumoto A, Thompson DC, Chen Y, Kitagawa K and Vasiliou V.
  • Journal Title: Environ Health Prev Med. Volume: 21 Issue: 6 Pages: 395-402
  • DOI: 10.1007/s12199-016-0579-2
  • NAID: 50010159078
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Long non-coding RNA, PANDA, contributes to the stabilization of p53 tumor suppressor protein. (2016)
  • Author(s): Kotake, Y., Kitagawa, K., Ohhata, T., Sakai, S., Uchida, C., Niida, H., Naemura, M. and Kitagawa, M.
  • Journal Title: Anticancer Res. Volume: 36 Issue: 1 Pages: 1605-1611
  • DOI: 10.21873/anticanres.11292
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Oncogenic Ras influences the expression of multiple lncRNAs. (2016)
  • Author(s): Kotake Y, Naemura M, Kitagawa K, Niida H, Tsunoda T, Shirasawa S, Kitagawa M.
  • Journal Title: Cytotechnology Volume: 68 Issue: 4 Pages: 1591-1596
  • DOI: 10.1007/s10616-014-9834-9
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The SCF-type E3 ubiquitin ligases as cancer targets. (2016)
  • Author(s): Kitagawa, K. and Kitagawa, M.
  • Journal Title: Curr. Cancer Drug Targets Volume: 16 Issue: 2 Pages: 119-29
  • DOI: 10.2174/1568009616666151112122231
  • Peer Reviewed
• [Journal Article] Regulation of GATA binding protein 2 levels via ubiquitin-dependent degradation by Fbw7: involvement of cyclin B-cyclin-dependent kinase 1-mediated phosphorylation of Thr176 in GATA binding protein 2. (2015)
  • Author(s): Nakajima T, Kitagawa K, Ohhata T, Sakai S, Uchida C, Shibata K, Minegishi N, Yumimoto K, Nakayama K-I, Masumoto K, Katou F, Niida H, Kitagawa M
  • Journal Title: J Biol Chem Volume: 290 Issue: 16 Pages: 10368-10381
  • DOI: 10.1074/jbc.m114.613018
  • Peer Reviewed / Open Access
• [Presentation] ブレオマイシン誘導性肺線維症モデルマウスにおいてユビキチンE3 リガーゼ Skp2の阻害は症状を軽減する (2018)
  • Author(s): 北川恭子 美甘真史 北川雅敏
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Behavioral anlysis of ALDH2 deficient mice. (2016)
  • Author(s): Toru Hosoi, Kohei Mori, Kyoko Kitagawa, Koichiro Ozawa
  • Organizer: the 18th International Symposium of Society for Aldh2 Knockout Mouse Research
  • Place of Presentation: Kitakyushu
  • Year and Date: 2016-11-16
  • Int'l Joint Research
• [Presentation] SCF-type E3 ligase Fbw7 plays pivotal roles in the maintenance of the development and commitment in hematopoietic cells. (2016)
  • Author(s): Kyoko Kitagawa, Masatoshi Kitagawa
  • Organizer: The 5th JCA-AACR Special Joint Conference
  • Place of Presentation: Urayasu
  • Year and Date: 2016-07-13
  • Int'l Joint Research
• [Presentation] CDK1によるリン酸化に依存した GATA2のFbw7による分解 (2015)
  • Author(s): 北川恭子 中嶋友美 北川雅敏
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] Fbw7による GATA2のユビキチン化分解機構 (2015)
  • Author(s): 北川恭子 中嶋友美 北川雅敏
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08