Elucidation of the DNA degradation mechanism during cornification and its application to drug discovery

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08296
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: University of Toyama
• Principal Investigator: Makino Teruhiko 富山大学, 学術研究部医学系, 准教授 (90359711)
• Co-Investigator(Kenkyū-buntansha): 清水 忠道 富山大学, 学術研究部医学系, 教授 (70260396)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: フィラグリン / DNA分解 / 細胞死 / カルパイン１ / ERH

Outline of Final Research Achievements

In this study, we examined the mechanism of DNA degradation by the N-terminus of profilaggrin (proFLG-ABT). We first investigated the involvement of DNase1L2, DNase2, TREX2, and CAD in this process. However, no involvement was observed. In contrast, in differentiated keratinocytes, the N terminus of proFLG and apoptosis inducing factor (AIF) were colocalized within the nucleus and the cells were positive for TUNEL staining. Furthermore, DNA degradation was significantly inhibited by the suppression of AIF.
In the analysis of proteins that can bind to proFLG-ABT within the nucleus, we investigated the expression of ERH, SOCS7, and eIF6, which were confirmed to be expressed in the normal epidermis. Furthermore, in cutaneous squamous cell carcinoma (SCC), ERH was strongly expressed in the nucleus of tumor cells, and the proliferation of SCC cells (HSC-1 cells) was inhibited by the suppression of ERH.

Free Research Field

表皮細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究の特色は角化において重要な役割を担うフィラグリンを中心に表皮角化細胞のDNA分解機序を解析したことである。近年表皮角化細胞の細胞死はコルネオトーシスと呼ばれる特殊な細胞死であることが提唱され、この細胞死の機序の全容解明は表皮細胞生物学の発展のみならず様々な疾患の病態の解明や新規治療の開発にもつながると思われる。本研究ではカルパイン1-AIF系の細胞死への関与やフィラグリンと核内で結合する分子の機能など多くの新知見が見出されており、学術的にも社会的にもこの領域の発展に大きく寄与するものと期待される。