TGF-β通过RAS效应器RREB1调节纤维化和发育性EMT
Jie Su1, Sophie M Morgani2,3, Charles J David1,4
1Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|January 10, 2020
概括
连接RAS和转化生长因子β (TGF-β) 途径以控制上皮细胞转化为介质酶 (EMT). 这一发现阐明了EMT如何推动发育,纤维化和癌症的进展.
科学领域:
- 细胞生物学
- 分子生物学
- 发育生物学
背景情况:
- 表皮转移到介质细胞转移 (EMT) 对于发育,伤口愈合,纤维化和癌症至关重要.
- 转化生长因子β (TGF-β) 信号,以及RAS和MAPK通路,驱动EMT.
- 失调的TGF-β信号和EMT与各种纤维性疾病和癌症有关.
研究的目的:
- 阐明在EMT诱导中协调RAS和TGF-β通路的分子机制.
- 确定整合这些信号级联的关键调节者.
- 了解这些综合途径在发育过程和病理状况中的作用.
主要方法:
- 研究了RAS响应元素结合蛋白1 (RREB1) 和TGFβ激活的SMAD转录因子之间的相互作用.
- 分析了由MAPK激活的RREB1对SNAIL转录因子的SMAD因素的招募.
- 检查了在EMT期间调节基因表达的上下文依赖的染色质可访问性.
主要成果:
- 确定RREB1是EMT中SMAD转录因子的关键合作伙伴.
- 已经证明MAPK激活的RREB1会对SNAIL产生SMAD因子.
- 显示RREB1和SMAD激活基于染色质可访问性的特定基因,驱动癌症中的纤维化EMT或发展中的中皮分化.
结论:
- RREB1作为RAS和TGF-β通路之间的分子桥梁,协调EMT.
- 这种机制解释了EMT在发育和疾病中的双重作用.
- 这些发现有助于更好地了解上皮质的可塑性及其在癌症和纤维化中的作用.
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