期刊
JOURNAL OF CELL SCIENCE
卷 115, 期 22, 页码 4227-4236出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.00091
关键词
claudin; E-cadherin; EGF; EMT; Erk; N-cadherin; occludin; TGF-beta; thyroid
类别
Enhancement of tumor cell growth and invasiveness by transforming growth factor-beta (TGF-beta) requires constitutive activation of the ras/MAPK pathway. Here we have investigated how MEK activation by epidermal growth factor (EGF) influences the response of fully differentiated and growth-arrested pig thyroid epithelial cells in primary culture to TGF-beta1. The epithelial tightness was maintained after single stimulation with EGF or TGF-beta1 (both 10 ng/ml) for 48 hours. In contrast, co-stimulation abolished the transepithelial. resistance and increased the paracellular flux of [H-3]inulin within 24 hours. Reduced levels of the tight junction proteins claudin-1 and occludin accompanied the loss of barrier function. N-cadherin, expressed only in few cells of untreated or single-stimulated cultures, was at the same time increased 30-fold and co-localised with E-cadherin at adherens junctions in all cells. After 48 hours of co-stimulation, both E- and N-cadherin were downregulated and the cells attained a fibroblastlike morphology and formed multilayers. TGF-beta1 only partially inhibited EGF-induced Erk phosphorylation. The MEK inhibitor U0126 prevented residual Erk phosphorylation and abrogated the synergistic responses to TGF-beta1 and EGE The observations indicate that concomitant growth factor-induced MEK activation is necessary for TGF-beta1 to convert normal thyroid epithelia] cells to a mesenchymal phenotype.
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