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Role of PPAR? and EGFR signalling in the urothelial terminal differentiation programme

Varley, C.L., Stahlschmidt, J., Lee, W.C., Holder, J., Diggle, C., Selby, P.J., Trejdosiewicz, L.K. and Southgate, J. (2004) Role of PPAR? and EGFR signalling in the urothelial terminal differentiation programme. Journal of Cell Science, 117 (10). pp. 2029-2036. ISSN 0021-9533

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Recently, considerable interest has focused on the ability of activated peroxisome proliferator-activated receptor (PPAR) to promote cytodifferentiation in adipocytes and some carcinoma cells; however, the role of PPAR in normal epithelial cytodifferentiation is unknown. Using uroplakin (UP) gene expression as a specific correlate of terminal urothelial cytodifferentiation, we investigated the differentiation-inducing effects of PPAR activation in normal human urothelial (NHU) cells grown as finite cell lines in monoculture. Two high-affinity activators of PPAR, troglitazone (TZ) and rosiglitazone (RZ) induced the expression of mRNA for UPII and UPIb and, to a lesser extent, UPIa. The specificity of the effect was shown by pretreating cells with a PPAR antagonist, GW9662, which attenuated the TZ-induced response in a dose-specific manner. The PPAR-mediated effect on UP gene expression was maximal when there was concurrent inhibition of autocrine-activated epidermal growth factor receptor (EGFR) signalling through either the phosphatidylinositol 3-kinase or extracellular signal-regulated kinase (ERK) pathways. The use of a specific EGFR tyrosine kinase inhibitor, PD153035, correlated with PPAR dephosphorylation and translocation to the nucleus, indicating a mechanism for regulating the balance between proliferation and differentiation. This is the first identification of specific factors involved in regulating differentiation-associated gene changes in urothelium and the first unambiguous evidence of a role for PPAR signalling in the terminal differentiation programme of a normal epithelium.

Item Type: Article
Institution: The University of York
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Oncology and Clinical Research (Leeds) > Oncolocy/Cancer Research UK Clinical Centre (Leeds)
The University of York > Biology (York)
Depositing User: York RAE Import
Date Deposited: 30 Apr 2009 15:44
Last Modified: 18 Jun 2015 17:28
Published Version: http://dx.doi.org/10.1242/jcs.01042
Status: Published
Publisher: Company of Biologist Ltd
Identification Number: 10.1242/jcs.01042
URI: http://eprints.whiterose.ac.uk/id/eprint/6522

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