KEAP1型
突变体
癌症研究
损失函数
体细胞
生物
细胞生物学
突变
细胞
函数增益
调节器
癌症
功能(生物学)
HEK 293细胞
细胞培养
表型
遗传学
基因
转录因子
作者
Joji Takahashi,Takafumi Suzuki,Miu Sato,Shuhei Nitta,Nahoko Yaguchi,Tsuyoshi Muta,Kouhei Tsuchida,Hiroko Suda,Masanobu Morita,Shin Hamada,Atsushi Masamune,Satoru Takahashi,Takashi Kamei,Masayuki Yamamoto
出处
期刊:Cell Reports
[Elsevier]
日期:2024-04-01
卷期号:43 (4): 114104-114104
标识
DOI:10.1016/j.celrep.2024.114104
摘要
Clinical evidence has revealed that high-level activation of NRF2 caused by somatic mutations in NRF2 (NFE2L2) is frequently detected in esophageal squamous cell carcinoma (ESCC), whereas that caused by somatic mutations in KEAP1, a negative regulator of NRF2, is not. Here, we aspire to generate a mouse model of NRF2-activated ESCC using the cancer-derived NRF2L30F mutation and cancer driver mutant TRP53R172H. Concomitant expression of NRF2L30F and TRP53R172H results in formation of NRF2-activated ESCC-like lesions. In contrast, while squamous-cell-specific deletion of KEAP1 induces similar NRF2 hyperactivation, the loss of KEAP1 combined with expression of TRP53R172H does not elicit the formation of ESCC-like lesions. Instead, KEAP1-deleted cells disappear from the esophageal epithelium over time. These findings demonstrate that, while cellular NRF2 levels are similarly induced, NRF2 gain of function and KEAP1 loss of function elicits distinct fates of squamous cells. The NRF2L30F mutant mouse model developed here will be instrumental in elucidating the mechanistic basis leading to NRF2-activated ESCC.
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