Identification and characterization of USP8 mutant target proteins in Cushing's disease

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08899
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• 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) ; 西岡 宏 (財)冲中記念成人病研究所, その他部局等, 研究員 (60218120) ; 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): 2020-04-01 – 2024-03-31
• Keywords: クッシング病 / USP8

Outline of Final Research Achievements

Somatic mutations in the deubiquitinating enzyme USP8 are highly prevalent in the ACTH-producing pituitary tumour Cushing's disease. However, the molecular mechanism is unknown. Comparison of gene expression profiles between wild-type WT and mutant MUT showed that MUT is activated in the MAPK pathway of PRKACA, MAP3K5 and MAPK13/14, and in the expression of clock genes such as NPAS2, PER2 and BMAL1, and that the expression levels of BMAL1 and PRKACA are highly correlated (R = 0.77). A high correlation was observed between the expression levels of BMAL1 and PRKACA with R=0.77. On the other hand, proteomic analysis revealed high expression of proteins involved in ACTH exocytosis such as synaptotagmin independently of mRNA expression.

Free Research Field

神経内分泌

Academic Significance and Societal Importance of the Research Achievements

Cushing 病はACTH・コルチゾールの概日リズム消失を伴う過剰分泌を特徴とするが、USP8変異体では時計遺伝子の過剰発現が生じ、特定のMAPK系を活性化してPOMC発現を誘導する可能性があること、 またACTHの開口分泌機構を調節する蛋白の高発現がACTHの過剰分泌に関与している可能性が考えられた。このことは臨床的にも変異体は野生型に比べPOMC発現が高いことと合致している。しかしながらUSP8変異体の標的蛋白は未だ不明であり今後の解明が望まれる。