Genetic programs of epithelial cell plasticity directed by transforming growth factor-β

Jiri Zavadil, Markus Bitzer, Dan Liang, Yaw Ching Yang, Aldo Massimi, Susanne Kneitz, Ester Piek, Erwin P. Böttinger

Research output: Contribution to journalArticle

402 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6686-6691
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number12
DOIs
StatePublished - Jun 5 2001

ASJC Scopus subject areas

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