Abstract
Recently, considerable interest has focused on the ability of activated peroxisome proliferator-activated receptor gamma (PPARgamma) to promote cytodifferentiation in adipocytes and some carcinoma cells; however, the role of PPARgamma 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 PPARgamma activation in normal human urothelial (NHU) cells grown as finite cell lines in monoculture. Two high-affinity activators of PPARgamma, 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 PPARgamma antagonist, GW9662, which attenuated the TZ-induced response in a dose-specific manner. The PPARgamma-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 PPARgamma 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 PPARgamma signalling in the terminal differentiation programme of a normal epithelium.
Original language | English |
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Pages (from-to) | 2029-2036 |
Number of pages | 8 |
Journal | Journal of Cell Science |
Volume | 117 |
Issue number | 10 |
Early online date | 30 Mar 2004 |
DOIs | |
Publication status | Published - 15 Apr 2004 |
Keywords
- differentiation
- kinase
- epidermal growth factor
- peroxisome proliferator activated receptor
- bladder
- uroplakin
- urothelium
- ACTIVATED-RECEPTOR-GAMMA
- UROPLAKIN GENE-EXPRESSION
- CELLS IN-VITRO
- TRANSCRIPTIONAL ACTIVATION
- LIGANDS SUPPRESS
- URINARY-BLADDER
- PROTEIN-KINASE
- CANCER CELLS
- TROGLITAZONE
- ROSIGLITAZONE