Genetic Programs of Epithelial Cell Plasticity Directed by Transforming Growth Factor-β

Epithelial-mesenchymal transitions (EMTs) are an essential manifestation of epithelial cell plasticity during morphogenesis, wound healing, and tumor progression. Transforming growth factor-β (TGF-β) modulates epithelial plasticity in these physiological contexts by inducing EMT. Here we report a tr...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-06, Vol.98 (12), p.6686-6691
Main Authors: Zavadil, Jiri, Bitzer, Markus, Liang, Dan, Yang, Yaw-Ching, Massimi, Aldo, Kneitz, Susanne, Piek, Ester, Böttinger, Erwin P.
Format: Article
Language:English
Subjects:
Actins
adherens junction
Adherens junctions
Biological Sciences
Cell Adhesion - drug effects
Cell growth
Cell motility
Cell Movement - drug effects
Cells, Cultured
Cellular biology
Cytoskeleton - physiology
Epithelial cells
Epithelial Cells - physiology
ERK protein
Gene expression regulation
Gene Expression Regulation - drug effects
Genes
Genetics
Human genetics
Humans
Integrins - physiology
Keratinocytes - physiology
Mitogen-Activated Protein Kinases - physiology
Progenitor cells
Proteins
Transcription, Genetic - drug effects
Transforming Growth Factor beta - pharmacology
Tumors
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Summary:Epithelial-mesenchymal transitions (EMTs) are an essential manifestation of epithelial cell plasticity during morphogenesis, wound healing, and tumor progression. Transforming growth factor-β (TGF-β) modulates epithelial plasticity in these physiological contexts by inducing EMT. Here we report a transcriptome screen of genetic programs of TGF-β-induced EMT in human keratinocytes and propose functional roles for extracellular response kinase (ERK) mitogen-activated protein kinase signaling in cell motility and disruption of adherens junctions. We used DNA arrays of 16,580 human cDNAs to identify 728 known genes regulated by TGF-β within 4 hours after treatment. TGF-β-stimulated ERK signaling mediated regulation of 80 target genes not previously associated with this pathway. This subset is enriched for genes with defined roles in cell-matrix interactions, cell motility, and endocytosis. ERK-independent genetic programs underlying the onset of EMT involve key pathways and regulators of epithelial dedifferentiation, undifferentiated transitional and mesenchymal progenitor phenotypes, and mediators of cytoskeletal reorganization. The gene expression profiling approach delineates complex context-dependent signaling pathways and transcriptional events that determine epithelial cell plasticity controlled by TGF-β. Investigation of the identified pathways and genes will advance the understanding of molecular mechanisms that underlie tumor invasiveness and metastasis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.111614398