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First published online 30 March 2004
doi: 10.1242/jcs.01042
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Research Article |
and EGFR signalling in the urothelial terminal differentiation programme
1 Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York YO10 5YW, UK
2 Cancer Research UK Clinical Centre, St James's University Hospital, Leeds LS9 7TF, UK
3 Department of Pathology, St James's University Hospital, Leeds LS9 7TF, UK
4 GlaxoSmithKline Pharmaceuticals, The Frythe, Welwyn, Hertfordshire, UK
* Author for correspondence (e-mail: js35{at}york.ac.uk)
Accepted 4 December 2003
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.
Key words: Differentiation, Kinase, Epidermal growth factor, Peroxisome proliferator activated receptor, Bladder, Uroplakin, Urothelium
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