Nuclear receptors (NR) are ligand dependent transcription factors. In the current study, expression of VDR and Farnesoid-X-receptor (FXR) protein is demonstrated along with relative mRNA expression of a range NRs and co-repressors in four bladder cancer cell lines. Nuclear co-repressor 1 (NCoR1) is over-expressed in RT-112 (1.6 fold) and EJ-28 cells (2.6 fold). This correlates with reduced sensitivity to NR ligands in EJ-28 cells. Stable over-expression of NCoR1 in sensitive RT-4 cells (lowest relative NCoR1 expression) led to reduced sensitivity to NR ligands; treatment with lithocholic acid (LCA - FXR and VDR ligand) led to expression of a cohort of genes consistent with a xenobiotic protective response (ABC transporter proteins, metabolizing enzymes and cell cycle arrest proteins) as assessed by microfluidic quantitative real-time reverse transcription polymerase chain reaction. NCoR1 over-expression was targeted with co-treatment with NR ligand and the histone deacetylase inhibitor Suberoylanilide hydroxamic acid (SAHA), resulting in strongly additive anti-proliferative responses to FXR, VDR and PPAR-γ ligands in NCoR1 over-expressing cells; confirmed as a G1/S phase cell cycle arrest in EJ-28. Microarray profiling revealed unique regulation of genes involved in cell proliferation. This study suggests NCoR1 acts as a selective regulator of NR function.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:512510 |
| Date | January 2010 |
| Creators | Abedin, Syed Asad |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/645/ |
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