Elucidation of molecular mechanisms of tumor initiation and progression by ribosomal stresses

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15211
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kobe University
• Principal Investigator: Otani Junji 神戸大学, 医学研究科, 助教 (10770878)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: Hippo経路 / 核小体ストレス

Outline of Final Research Achievements

During the last decade, increasing attention has been focused on the nucleolar stress pathway that releases ribosomal proteins from the nucleolus to the nucleoplasm when ribosome biosynthesis is abnormal and suppresses cell proliferation through p53 activation. On the other hand, it has been suggested that an abnormality in the ribosomal protein gene may promote canceration in studies of ribosomal protein mutants with Zebrafish model system and in epidemiological studies of ribosomopathy patients. In this study, we found that transcriptional inhibition of ribosomal RNA by an RNA polymerase inhibitor actinomycin D enhances the expression of down-stream target genes of the oncogenic transcriptional co-factors YAP1/TAZ and nuclear accumulation of YAP1 protein. Promoting effect of actinomycin D on the oncogenic growth signaling pathway may underlie the cancer promoting effect of ribosomal stress conditions and ribosomopathies.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

本研究により、エネルギーの最大の消費過程であるリボソーム生合成過程と、近年がん治療の標的として大きな注目を浴びているHippo-YAP経路の関連が示唆された。これはリボソーム病の病態把握のみならず、リボソーム病に起因する悪性疾患の治療薬開発にもつながる可能性がある。また一般のがん細胞の多くでも、染色体異数性に伴うリボソーマル蛋白質遺伝子のコピー数変化や、発現異常がみられ、核小体ストレス作動状態にあると考えられる。そのため、本研究が、幅広いがんの病態把握や治療薬開発の一助になることも期待できる。