Post-translational modification of transcription factors regulates on-off switch of cell proliferation

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K09464
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tohoku University
• Principal Investigator: Minegishi Naoko 東北大学, 東北メディカル・メガバンク機構, 教授 (40271895)
• Co-Investigator(Kenkyū-buntansha): 勝岡 史城 東北大学, 東北メディカル・メガバンク機構, 准教授 (30447255)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 血液腫瘍学 / 転写因子 / GATA因子 / 細胞周期制御 / 翻訳後調節

Outline of Final Research Achievements

GATA2 is an essential transcription factor for hematopoiesis. We analyzed the cell-cycle dependent post-translational regulation of this factor. The expression level of GATA2 and its binding to target sequences, were low in early G1 phase, then increased in G1-S transition phase. In the late S phase, GATA2 expression increased but GATA2 binding to its target sequences decreased. In M-phase, Cyclin B1-Cyclin-dependent kinase (CDK)1 phosphorylated T176 residue of GATA2, and induced the interaction with F-box/WD repeat -containing protein 7 (Fbw7) and the ubiquitin-mediated degradation of GATA2. GATA2 was also phosphorylated by Cyclin A/E-CDK2 and interacted with S-phase kinase-associated protein 2 (Skp2), which is known as a ubiquitin-conjugating enzyme of phosphorylated cyclin-dependent kinase inhibitor 1B (p27) in G1-S phase. Thus, GATA2 is under the regulation of cell-cycle specific serine/threonine phosphorylation and ubiquitin-mediated degradation.

Free Research Field

血液学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

GATA2は多くの造血器腫瘍に発現するほか、GATA２欠損症では前白血病から白血病の発症や、血液・免疫系の細胞の減少による免疫不全状態が報告されている。一方、ユビキチン・プロテアソーム系は造血器腫瘍治療の重要な標的経路であり、本課題の成果を発端として、今後、この経路とGATA２による細胞増殖のより詳細な関係が明らかにされ、これら疾患の病態解明や治療法の開発につながることが期待される。