Role of dysregulation of zinc-dependent proteostasis signaling in zinc deficiency

2022 Fiscal Year Final Research Report

• Project/Area Number: 18K06957
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Juntendo University (2020-2022); Kobe University (2018-2019)
• Principal Investigator: Edamatsu Hironori 順天堂大学, 医学部, 准教授 (70335438)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: RAS / がん / 脆弱性 / 小胞体ストレス / 亜鉛恒常性 / トランスクリプトーム / 細胞死 / タンパク質恒常性

Outline of Final Research Achievements

Expression of constitutively active Hras (HrasG12V) under zinc-deficient conditions led to the activation of caspase-3 and stress-activated MAPKs (JNK and p38MAPK). The induction of these stress responses depended on the activation of ERK, which is downstream of Ras. HrasG12V expression induced endoplasmic reticulum (ER) stress, which was further exacerbated by zinc deficiency to activate JNK and p38MAPK through IRE1. In addition, HrasG12V expression upregulated the expression of a subset of zinc-binding proteins, which appears to dysregulate zinc homeostasis and proteostasis and to confer vulnerability to zinc deficiency.

Free Research Field

細胞内シグナル伝達

Academic Significance and Societal Importance of the Research Achievements

亜鉛欠乏下でのRasシグナルの恒常的活性化が引き起こす細胞死の誘導機構の解析を目指した本研究は、細胞の生存における亜鉛恒常性の重要性を見出した。さらに、Rasシグナル伝達の異常な亢進が亜鉛結合タンパク質の生合成を亢進させ、その結果、亜鉛恒常性を破綻させる可能性を指摘することができた。今後、本研究で得られた成果をさらに発展させることで、がん細胞の新たな脆弱性の発見に繋がると思われる。