| Autor: |
Varley, Claire K., Stahlschmidt, Jens, Wen-Chun Lee, Holder, Julie, Diggle, Christine, Selby, Peter J., Trejdosiewicz, Ludwik K., Southgate, Jennifer |
| Předmět: |
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| Zdroj: |
Journal of Cell Science; 4/15/2004, Vol. 117 Issue 10, p2029-2036, 8p, 1 Color Photograph, 3 Black and White Photographs, 3 Diagrams, 6 Graphs |
| Abstrakt: |
Recently, considerable interest has focused on the ability of activated peroxisome proliferator-activated receptor y (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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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