Role of PPARgamma and EGFR signalling in the urothelial terminal differentiation programme

C L Varley, J Stahischmidt, W C Lee, J Holder, C Diggle, P J Selby, L K Trejdosiewicz, J Southgate

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)2029-2036
Number of pages8
JournalJournal of Cell Science
Volume117
Issue number10
Early online date30 Mar 2004
DOIs
Publication statusPublished - 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

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