Elucidation of novel molecular mechanisms in the regulation of stress-responsive signaling by cross talk of various post-translational modifications

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02567
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Matsuzawa Atsushi 東北大学, 薬学研究科, 教授 (80345256)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 翻訳後修飾 / シグナル伝達 / ストレス応答 / リン酸化 / ユビキチン化

Outline of Final Research Achievements

The strict regulation of duration and intensity of activation of the stress response signaling is required for the induction of appropriate responses to various types of internal and external stress, and its failure causes cellular dysfunction and various diseases. However, the molecular mechanisms of the regulation are not well understood. In this study, we found that the balance of the stress response signaling is actually regulated and fine-tuned through the crosstalk (cooperative and reciprocal interaction) between various post-translational modifications, such as ubiquitination, for kinases as signaling molecules essential for the induction of stress responses, including cell death and inflammation, and that the disorder of the balance could lead to the onset of cancer and autoimmune diseases.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

様々な内外環境ストレスに適応し、細胞死や炎症などの適切なストレス応答を誘導することで、生体や細胞はその恒常性を維持しているため、ストレス応答シグナルのバランスが破綻すると多様な疾患に陥る。本研究において、ストレス応答シグナルのバランス制御が、キナーゼのようなストレス応答シグナル分子に対する、ユビキチン化等の多彩な翻訳後修飾のクロストークで実際に制御・微調整されることを見出し、そのユビキチン化酵素やキナーゼ分子の異常が癌・自己免疫疾患等の発症に結び付く可能性を示せた点は、それらの疾患の原因解明と具体的な新規創薬標的分子の特定に繋がり、新規疾患治療戦略の提言を可能とする重要な研究成果である。