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

Journal of Cell Science - Tập 117 Số 10 - Trang 2029-2036 - 2004
Claire L. Varley1, Jens Stahlschmidt2,3, Wen‐Chun Lee1, Julie C. Holder4, Christine P. Diggle2,1, Peter J. Selby2, L K Trejdosiewicz2, Jennifer Southgate1
1Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York YO10 5YW, UK
2Cancer Research UK Clinical Centre, St James's University Hospital, Leeds LS9 7TF, UK
3Department of Pathology, St.James's University Hospital, Leeds, LS9 7TF, UK
4GlaxoSmithKline Pharmaceuticals, The Frythe, Welwyn, Hertfordshire, UK

Tóm tắt

Recently, considerable interest has focused on the ability of activated peroxisome proliferator-activated receptor γ (PPARγ) to promote cytodifferentiation in adipocytes and some carcinoma cells; however, the role of PPARγ 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 PPARγ activation in normal human urothelial (NHU) cells grown as finite cell lines in monoculture. Two high-affinity activators of PPARγ, 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 PPARγ antagonist, GW9662, which attenuated the TZ-induced response in a dose-specific manner. The PPARγ-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 PPARγ 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 PPARγ signalling in the terminal differentiation programme of a normal epithelium.

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Journal of Cell Science

Tập 117 Số 10

2029-2036

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