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 0021-9533Full text not available from this repository.
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.
|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:||29 Sep 2010 14:23|
|Publisher:||Company of Biologist Ltd|