Elucidation of signal transduction mediated by target protein(s) of USP8 mutation in Cushing's disease

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09895
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Okinaka Memorial Institute for Medical Research
• Principal Investigator: TAKESHITA AKIRA (財)冲中記念成人病研究所, その他部局等, 研究員 (20322646)
• Co-Investigator(Kenkyū-buntansha): 竹内 靖博 (財)冲中記念成人病研究所, その他部局等, 研究員 (50202164) ; 山田 正三 (財)冲中記念成人病研究所, その他部局等, 研究員 (80260131)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: クッシング病 / Cushing病 / USP8

Outline of Final Research Achievements

Cushing's disease (CD) is designated as an intractable disease by the Ministry of Health, Labor and Welfare. CD is caused by a pituitary adenoma characterized by excessive secretion of ACTH due to loss of circadian rhythm of ACTH. Somatic mutations in the deubiquitinase USP8 are found in about half of the tumors, but the mechanism by which the mutations cause the disease remains unclear. We investigated using a method called DNA microarray and found that USP8 mutation-positive tumors overexpress the group of clock genes and correlate with the expressions of specific mitogen-activated protein kinase (MAPK) pathway and ACTH precursor, POMC. We conclude that the loss of ACTH circadian rhythm in CD may be related to the activation of the clock genes.

Free Research Field

内分泌代謝学

Academic Significance and Societal Importance of the Research Achievements

クッシング病はACTHの概日リズムの消失によるACTHの過剰分泌を特徴とするが、USP8変異による時計遺伝子群の活性化と特定の分裂促進因子活性化タンパク質キナーゼ（MAPK）経路の活性化との関連性が示唆された。USP8変異を介した特定の遺伝子の活性化が明らかになると、それらを標的とする薬物治療にも繋がる可能性が高い。さらには時計遺伝子の発現を調節し、USP8 の基質となる蛋白が明らかとなると，Cushing病の新たな発症機構の解明にも役立つ。