Abstract
The peroxisome proliferator-activated receptor c (PPAR gamma) is a ligand-activated transcription factor that has been implicated in the induction of differentiation of various cell types, including human uroepithelial cells. PPAR gamma-mediated differentiation of normal human urothelial (NHU) cells in vitro requires coinhibition of epidermal growth factor receptor ( EGFR) signalling and is characterised by de novo expression of late/terminal differentiation-associated genes, including uroplakins (UPK), over a 6-day period. We used gene microarrays to identify intermediary transcription factors induced in direct response to PPAR gamma activation of EGFR-inhibited NHU cells. FOXA1 and IRF-1 contained consensus cognate binding sites in UPK1a, UPK2, and UPK3a promoters and transcripts were induced within 12 h of PPAR gamma activation; transcription complex formation was confirmed by electromobility shift assays. In urothelium in situ, both FOXA1 and IRF-1 were nuclear and expressed in a differentiation-associated pattern. Knockdown by transient siRNA of either FOXA1 or IRF-1 abrogated PPAR gamma-induced uroplakin expression in vitro. This is the first evidence that ligand activation of PPAR gamma induces expression of intermediary transcription factors that mediate an epithelial differentiation programme and represents a new paradigm for understanding differentiation, regenerative repair and inflammation in epithelial tissues.
| Original language | English |
|---|---|
| Pages (from-to) | 103-114 |
| Number of pages | 12 |
| Journal | Cell death and differentiation |
| Volume | 16 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2009 |
Keywords
- differentiation
- PPAR gamma
- interferon regulatory factor
- forkhead box
- bladder
- epithelium
- ACTIVATED-RECEPTOR-GAMMA
- HEPATOCYTE NUCLEAR FACTOR-3-ALPHA
- UROPLAKIN GENE-EXPRESSION
- CELLS IN-VITRO
- RETINOIC ACID
- TERMINAL DIFFERENTIATION
- LIGANDS SUPPRESS
- BLADDER
- PROMOTER
- PROLIFERATION