TGF-β orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1
| Autor: | Ekrem Emrah Er, Weiping Shu, Sophie M. Morgani, Yun-Han Huang, Harihar Basnet, Qiong Wang, Yilong Zou, Charles J. David, Ronald C. Hendrickson, Joan Massagué, Anna-Katerina Hadjantonakis, Jie Su, Rajesh K. Soni |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Epithelial-Mesenchymal Transition Smad Proteins SMAD Biology Article 03 medical and health sciences Mice 0302 clinical medicine Fibrosis Transforming Growth Factor beta Cell Line Tumor Neoplasms Renal fibrosis medicine Animals Humans Transcription factor Multidisciplinary Effector Gastrulation Epithelial Cells medicine.disease Cell biology Chromatin DNA-Binding Proteins Organoids 030104 developmental biology 030220 oncology & carcinogenesis embryonic structures ras Proteins Female Snail Family Transcription Factors Mitogen-Activated Protein Kinases Transforming growth factor Transcription Factors |
| Zdroj: | Nature |
| ISSN: | 1476-4687 |
| Popis: | Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer1–4. EMTs are driven by SNAIL, ZEB and TWIST transcription factors5,6 together with microRNAs that balance this regulatory network7,8. Transforming growth factor β (TGF-β) is a potent inducer of developmental and fibrogenic EMTs4,9,10. Aberrant TGF-β signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer4,11. TGF-β depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs12–19. 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-β-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-β-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-β–SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal–SMAD 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-β 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-β pathways regulate distinct modes of epithelial-to-mesenchymal transition via RAS-responsive element binding protein 1. |
| Databáze: | OpenAIRE |
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