REGULATORY ACTION OF TPR DOMAIN PROTEINS ON THE ANDROGEN RECEPTOR

HANSEN V; RUBINO C; SOL CIUCCI; GALIGNIANA MD; MAZAIRA G; SM

Congreso; LXVII Reunión Anual de SAIC; 2022

Tetratricopeptide repeat (TPR) domains are arrangements of 34 amino acids organized in tandems of antiparallel α-helices. They are involved in protein-protein interactions. The best characterized TPR proteins are those belonging to steroid receptor complexes. Our laboratory has previously demonstrated that the TPR-domain immunophilins FKBP51 and FKBP52 regulate the glucocorticoid receptor (GR) response in antagonistic fashion, as well as other TPR proteins do such as PP5, SGT1α and 14-3-3σ. The aim of this work was to extend those studies to the regulation of the androgen receptor (AR). The nuclear import rate of the AR was analyzed by fluorescence microscopy, and the transcriptional activity by reporter gene assays. The results show that, similar to the case of GR, both FKBP52 and PP5 stimulate AR transcriptional activity. On the other hand, SGT1α shows a slight inhibitory effect on AR, which contrasts with the strong inhibition observed for GR. Regarding 14-3-3σ, there is a concentration-dependent inhibitory action on AR transcriptional activity, unlike the biphasic regulation observed for GR (i.e. stimulation for low levels of expression followed by inhibition at higher levels). Microscopy studies showed that, in contrast to our expectations, the subcellular localization of AR was not influenced by any of these proteins, which represents an important contrast with the transport of the GR, which is greatly affected by TPR proteins. In conclusion, it is demonstrated that different TPR domain proteins function as regulatory factors of the transcriptional activity of AR. Their actions are not necessary alike to those shown for the GR, which indicates specificity of action for each receptor. Therefore, the expression balance between these TPR factors may determine the final biological response, which could be critical. For example, in prostate cancer cells the balance of activity between AR and GR greatly affects the development and progression of the pathology.