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Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-beta1 involves MAPK, Smad and AP-1 signalling pathways.
J Cell Biochem. 2005 Aug 01; 95(5):918-31.JC

Abstract

Recent data indicate that transforming growth factor-beta1 (TGF-beta1) can act to promote tumour progression in the late stages of carcinogenesis. The mechanism by which this occurs is unknown although a ligand-induced epithelial-mesenchymal transition (EMT) is thought to be important. In this study, we demonstrate that active Ras is required for TGF-beta1-induced EMT in human keratinocytes and that epidermal growth factor (EGF) can substitute for mutant Ras. EMT was reversed by the removal of TGF-beta1. Under conditions of TGF-beta1-induced EMT, cells were growth inhibited by the ligand resulting in G1 arrest. In cells containing normal Ras, TGF-beta1-activated ERK and p38 mitogen-activated protein kinases (MAPKs), and levels of activation were further increased by co-treatment with EGF. Inhibition of MAPK pathways and Smad2/3 signalling blocked the induction of EMT by TGF-beta1. Further, inhibition of the AP-1 transcriptional complex by [6]-Gingerol, or by the ectopic expression of JDP2, blocked TGF-beta1-induced EMT and conversely, stimulation of AP-1 by 12-O-tetradecanoylphorbol 13-acetate (TPA) substituted for EGF in the induction of EMT by TGF-beta1 in cells containing normal Ras. The presence of oncogenic Ras, the treatment of cells with EGF, or the treatment of cells with TPA to activate AP-1, potentiated TGF-beta1-induced Smad-dependent transcription, an effect that was attenuated by the inhibition of MAPKs and AP-1. The results demonstrate that active Ras and TGF-beta1 co-operate to reversibly induce EMT in human keratinocytes by mechanisms that involve MAPKs, Smad2/3 and AP-1. Further we demonstrate that MAPK/AP-1 signalling enhances Smad transcriptional activity under conditions associated with TGF-beta1-induced EMT.

Authors+Show Affiliations

Department of Oral and Dental Science, University of Bristol, Bristol BS1 2LY, United Kingdom. maria.davies@bristol.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15861394

Citation

Davies, Maria, et al. "Induction of an Epithelial to Mesenchymal Transition in Human Immortal and Malignant Keratinocytes By TGF-beta1 Involves MAPK, Smad and AP-1 Signalling Pathways." Journal of Cellular Biochemistry, vol. 95, no. 5, 2005, pp. 918-31.
Davies M, Robinson M, Smith E, et al. Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-beta1 involves MAPK, Smad and AP-1 signalling pathways. J Cell Biochem. 2005;95(5):918-31.
Davies, M., Robinson, M., Smith, E., Huntley, S., Prime, S., & Paterson, I. (2005). Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-beta1 involves MAPK, Smad and AP-1 signalling pathways. Journal of Cellular Biochemistry, 95(5), 918-31.
Davies M, et al. Induction of an Epithelial to Mesenchymal Transition in Human Immortal and Malignant Keratinocytes By TGF-beta1 Involves MAPK, Smad and AP-1 Signalling Pathways. J Cell Biochem. 2005 Aug 1;95(5):918-31. PubMed PMID: 15861394.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-beta1 involves MAPK, Smad and AP-1 signalling pathways. AU - Davies,Maria, AU - Robinson,Max, AU - Smith,Emily, AU - Huntley,Suzy, AU - Prime,Stephen, AU - Paterson,Ian, PY - 2005/4/30/pubmed PY - 2005/10/19/medline PY - 2005/4/30/entrez SP - 918 EP - 31 JF - Journal of cellular biochemistry JO - J Cell Biochem VL - 95 IS - 5 N2 - Recent data indicate that transforming growth factor-beta1 (TGF-beta1) can act to promote tumour progression in the late stages of carcinogenesis. The mechanism by which this occurs is unknown although a ligand-induced epithelial-mesenchymal transition (EMT) is thought to be important. In this study, we demonstrate that active Ras is required for TGF-beta1-induced EMT in human keratinocytes and that epidermal growth factor (EGF) can substitute for mutant Ras. EMT was reversed by the removal of TGF-beta1. Under conditions of TGF-beta1-induced EMT, cells were growth inhibited by the ligand resulting in G1 arrest. In cells containing normal Ras, TGF-beta1-activated ERK and p38 mitogen-activated protein kinases (MAPKs), and levels of activation were further increased by co-treatment with EGF. Inhibition of MAPK pathways and Smad2/3 signalling blocked the induction of EMT by TGF-beta1. Further, inhibition of the AP-1 transcriptional complex by [6]-Gingerol, or by the ectopic expression of JDP2, blocked TGF-beta1-induced EMT and conversely, stimulation of AP-1 by 12-O-tetradecanoylphorbol 13-acetate (TPA) substituted for EGF in the induction of EMT by TGF-beta1 in cells containing normal Ras. The presence of oncogenic Ras, the treatment of cells with EGF, or the treatment of cells with TPA to activate AP-1, potentiated TGF-beta1-induced Smad-dependent transcription, an effect that was attenuated by the inhibition of MAPKs and AP-1. The results demonstrate that active Ras and TGF-beta1 co-operate to reversibly induce EMT in human keratinocytes by mechanisms that involve MAPKs, Smad2/3 and AP-1. Further we demonstrate that MAPK/AP-1 signalling enhances Smad transcriptional activity under conditions associated with TGF-beta1-induced EMT. SN - 0730-2312 UR - https://www.unboundmedicine.com/medline/citation/15861394/Induction_of_an_epithelial_to_mesenchymal_transition_in_human_immortal_and_malignant_keratinocytes_by_TGF_beta1_involves_MAPK_Smad_and_AP_1_signalling_pathways_ L2 - https://doi.org/10.1002/jcb.20458 DB - PRIME DP - Unbound Medicine ER -