Extensive influence on malignancy by cancer specific mature mRNA re-splicing

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07182
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Fujita Health University
• Principal Investigator: Kameyama Toshiki 藤田医科大学, 医学部, 講師 (60298544)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: mRNA再スプライシング / エクソン・ジャンクション複合体 / RBM4a / エキシトロン / がん

Outline of Final Research Achievements

We have demonstrated a novel two-step splicing process in which normally spliced TSG101 mRNA is re-spliced to generate aberrant TSG101 mRNA in cancer cells .The mRNA re-splicing implies an important mechanism that prevents deleterious extra re-splicing in normal cells. The control of the re-splicing could be promoted by unknown activator upregulated and/or repressor downregulated in cancer cells. To identify repressor candidates of mRNA re-splicing, we screened siRNA library. As a result, we have identified RBM4a and EIF4A3 proteins as a mRNA re-splicing repressor. RBM4a is also known as a tumor suppressor via controlling apoptosis, proliferation and migration. On the other hand, EIF4A3 is well known as a core factor of the exon junction complex (EJC). We postulate that global prevention of aberrant mRNA re-splicing, termination of splicing precisely, is critical for the consequent tumor suppression. These factors could be key factors to prove this hypothesis.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

これまで、スプライシング反応が完了すると、mRNA上にはまだスプライス部位が残存するにもかかわらず、直ちに核外に輸送されタンパク質に翻訳されると考えられてきた。本研究で我々の発見した結果は、正常細胞にはスプライシング反応をきちんと停止させる機構が存在する事を新たに示唆した。
そして、その機構が破綻すると、細胞のトランスクリプトームを破綻させることにつながる事も示し、その大規模な破綻が細胞がん化など重大な疾患に結びつく可能性を示唆した点が重要である。