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Project

New therapeutic targets in the dimerization modes that drive androgen receptor functioning

The androgen receptor (AR) is a ligand-inducible transcription factor. It has three domains: an aminoterminal domain (NTD), a central DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD). Like many transcription factors, the AR has to dimerise in order to find the DNA response elements in the genome. However, the AR has three independent dimerization mechanisms: via the DBD, via the LBD, and via so-called N/C interactions. In vitro studies resulted in inconclusive and apparent contradictory observations. We therefore first investigate the in vivo role of each of these dimerizations by analyzing the effects of loss of function mutations in rodent models. The in vivo data are a starting point to inspire further in vitro analysis in cell lines at the level of gene expression control and chromatin binding, as well as further biophysical approaches and structural studies. For the LBD dimerization, this will include studying the effects of small molecule inhibitors. Ultimately, this basic research project will deliver new insights in AR molecular biology which will be translatable in applications that target the AR during the treatment of advanced lethal forms of prostate cancer

Date:1 Oct 2022 →  Today
Keywords:Androgen receptor
Disciplines:Andrology
Project type:PhD project