Regulation of inflammatory response via ubiquitin-dependent degradation by Fbw7

2018 Fiscal Year Final Research Report

• 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
• Keywords: Fbw7 / 炎症

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.

Free Research Field

分子生物学

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。