Regulation of the androgen receptor function by TPR-domain proteins

HANSEN, V.; RUBINO, C.; CIUCCI, S.; ERLEJMAN, A.G.; GALIGNIANA, M.D.; MAZAIRA, G.I.

Mar del Plata

Congreso; LXVII Reunión anual de la Sociedad Argentina de Investigación Clínica(SAIC); 2022

Sociedad Argentina de Investigación Clínica

Tetratricopeptide repeats (TPR) sequences of 34 amino acids arranged in tandems of antiparallel α-helices. They are responsible of protein-protein interactions. The best characterized TPR proteins are those found associated to Hsp90 in steroid receptor complexes. In previous works, our laboratory demonstrated that the main TPR-domain immunophilins FKBP51 and FKBP52 regulate the activity of the glucocorticoid receptor (GR) in a competitive fashion with other coexisting TPR proteins, such as PP5, SGT1α and 14-3-3σ. In this work, the study was extended to the androgen receptor (AR). The nuclear import of AR was evidenced by fluorescence microscopy, and the transcriptional activity was assessed by a luciferase reporter gene. Like for the case GR, the results demonstrate that both FKBP52 and PP5 enhance AR transcriptional activity, whereas SGT1α only shows a slight inhibitory effect on AR rather than the strong stimulation measured for GR. Regarding 14-3-3σ, an expression-dependent inhibitory effect was measured for AR, unlike the biphasic regulation previously observed for GR (i.e., stimulation at for low expression levels and inhibitory action for high levels). Microscopy studies showed that, in contrast to our expectations, the subcellular localization of AR was unaffected by the proteins tested here. In conclusion, TPR domain proteins regulate the transcriptional activity of AR showing patterns that differ from those of GR. This indicates receptor specificity of action. It is also implied that the expression balance between all these TPR factors should affect the final biological response. This may be relevant for cases like prostate cancer, where the functional balance between AR and GR affects the development and progression of the pathology.