小柯机器人

研究揭示调控纤维化和发育中EMT的分子机制
2020-01-10 14:33

美国纪念斯隆凯特林癌症研究所Joan Massagué研究团队发现,TGF-β通过RAS效应蛋白RREB1协调纤维化和发育中的EMT。2020年1月8日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示,上皮-间充质转变(EMT)是表型可塑性过程,在发育、伤口愈合、纤维化和癌变过程中赋予上皮细胞迁移和侵袭特性。EMT受SNAIL、ZEB和TWIST转录因子以及平衡该调节网络的小RNA所驱动。转化生长因子β(TGF-β)是发育和纤维化EMT的有效诱导因子。异常的TGF-β信号和EMT与肾纤维化、酒精性肝病、非酒精性脂肪性肝炎、肺纤维化和癌症的发病机制有关。TGF-β依赖于RAS和丝裂原活化蛋白激酶(MAPK)途径输入来诱导EMT。

研究人员报道了这些信号如何协同触发EMT,并将其与更广泛的病理生理过程整合。研究人员确定RAS反应元件结合蛋白1(RREB1)、RAS转录效应子作为EMT中TGF-β激活的SMAD转录因子的关键伴侣。MAPK激活的RREB1将TGF-β激活的SMAD因子募集到SNAIL。条件依赖性染色质可及性引导RREB1和SMAD激活其他基因,从而决定了EMT的产生。在癌细胞中,TGF-β–SMAD和RREB1直接驱动SNAIL和刺激成纤维细胞,促进肿瘤内纤维化并支持肿瘤生长的纤维化因子的表达。在小鼠表皮祖细胞中,Nodal–SMAD和RREB1结合诱导SNAIL和中胚层分化基因的表达,从而驱动原肠胚运动。因此,RREB1提供RAS和TGF-β途径之间的分子联系,从而协同诱导发育性和纤维化EMT。这些发现加深了人们对上皮可塑性的调节及其在发育、纤维化和癌症中病理作用的理解。
 
附:英文原文

Title: TGF-β orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1

Author: Jie Su, Sophie M. Morgani, Charles J. David, Qiong Wang, Ekrem Emrah Er, Yun-Han Huang, Harihar Basnet, Yilong Zou, Weiping Shu, Rajesh K. Soni, Ronald C. Hendrickson, Anna-Katerina Hadjantonakis, Joan Massagu

Issue&Volume: 2020-01-08

Abstract: Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer14. EMTs are driven by SNAIL, ZEB and TWIST transcription factors5,6 together with microRNAs that balance this regulatory network7,8. Transforming growth factor  (TGF-) is a potent inducer of developmental and fibrogenic EMTs4,9,10. Aberrant TGF- signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer4,11. TGF- depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs1219. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector20,21, as a key partner of TGF--activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF--activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, NodalSMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF- pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer. RAS and TGF- pathways regulate distinct modes of epithelial-to-mesenchymal transition via RAS-responsive element binding protein 1.

DOI: 10.1038/s41586-019-1897-5

Source:https://www.nature.com/articles/s41586-019-1897-5

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0