| Autor: |
Koushyar, S., Economides, G., Zaat, S., Jiang, W., Bevan, C. L., Dart, D. A. |
| Přispěvatelé: |
Cancer Research UK, Prostate Cancer UK, Medical Microbiology and Infection Prevention |
| Jazyk: |
angličtina |
| Rok vydání: |
2017 |
| Předmět: |
|
| Zdroj: |
Oncogenesis, 6(5). Nature Publishing Group |
| ISSN: |
2157-9024 |
| Popis: |
Prohibitin (PHB) is a tumour suppressor molecule with pleiotropic activities across several cellular compartments including\ud mitochondria, cell membrane and the nucleus. PHB and the steroid-activated androgen receptor (AR) have an interplay where AR\ud downregulates PHB, and PHB represses AR. Additionally, their cellular locations and chromatin interactions are in dynamic\ud opposition. We investigated the mechanisms of cell cycle inhibition by PHB and how this is modulated by AR in prostate cancer.\ud Using a prostate cancer cell line overexpressing PHB, we analysed the gene expression changes associated with PHB-mediated cell\ud cycle arrest. Over 1000 gene expression changes were found to be significant and gene ontology analysis confirmed PHB-mediated\ud repression of genes essential for DNA replication and synthesis, for example, MCMs and TK1, via an E2F1 regulated pathway—\ud agreeing with its G1/S cell cycle arrest activity. PHB is known to inhibit E2F1-mediated transcription, and the PHB:E2F1 interaction\ud was seen in LNCaP nuclear extracts, which was then reduced by androgen treatment. Upon two-dimensional western blot analysis,\ud the PHB protein itself showed androgen-mediated charge differentiation (only in AR-positive cells), indicating a potential\ud dephosphorylation event. Kinexus phosphoprotein array analysis indicated that Src kinase was the main interacting intracellular\ud signalling hub in androgen-treated LNCaP cells, and that Src inhibition could reduce this AR-mediated charge differentiation. PHB\ud charge change may be associated with rapid dissociation from chromatin and E2F1, allowing the cell cycle to proceed. The AR and\ud androgens may deactivate the repressive functions of PHB upon E2F1 leading to cell cycle progression, and indicates a role for AR\ud in DNA replication licensing. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
