A novel regulatory mechanism of the function of tumor suppressor p27 by a nucleolar protein NPM1.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K05510
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 38060:Applied molecular and cellular biology-related
• Research Institution: Tokyo University of Agriculture
• Principal Investigator: CHIBAZAKURA TAKU 東京農業大学, 生命科学部, 教授 (30227334)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 細胞増殖制御 / p27 / NPM1 / ARF / p53 / タンパク質分解 / 細胞遊走・浸潤能 / がん転移

Outline of Final Research Achievements

The dysfunction of the cyclin-dependent kinase inhibitor/tumor suppressor p27 is one of the contributing factors to carcinogenesis. In this study, we elucidated that NPM1, a p27-interacting factor highly expressed in cancers, suppresses p27 function by trapping it in the nucleolus. Additionally, we revealed that another tumor suppressor, ARF, restores p27 function by inhibiting NPM1. We also discovered that p27 protein degradation is accelerated in the absence of the major tumor suppressor p53 and suggest that p53 negatively regulates two pathways of p27 degradation. Furthermore, we demonstrated that induction of p27 expression in cancer cells not only inhibits cell proliferation but also suppresses factors contributing to cancer malignancy, such as cell migration, invasion, and metastatic potential.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究で示されたNPM1によるp27機能制御機構は、p27を十分量発現していながら増殖が正常に制御されないがん細胞におけるp27の機能抑圧機構とともに、その抑圧を打ち消すがん抑制因子ARFの重要性を示唆するものとして新規性・学術的意義ともに高い。また、がん細胞でNPM1-p27相互作用を阻害することでp27機能を回復させるような新規抗がん戦略への応用も期待され、社会的意義も高い。さらに、最も主要ながん抑制因子p53によるp27安定化機構、およびp27が転移に関わるがん悪性化要因を抑制する機能を新規に見出したことは、p27を軸とするがん抑制ネットワークの理解に大きく貢献するものである。