Regulation of AR and GR biological response by TPR-domain proteins.

MAZAIRA G.I.; MARTÍNEZ-DORR A; MAZAIRA G.I.; MARTÍNEZ-DORR A; CIUCCI, S.; ERLEJMAN A.G.; CIUCCI, S.; ERLEJMAN A.G.; ROZOWYKWIAT E; GALIGNIANA M.D.; ROZOWYKWIAT E; GALIGNIANA M.D.

San Diego

Congreso; Ninth International Congress On Stress Responses In Biology & Medicine; 2019

Cell Stress Society International

The best characterized proteins that show TPR domains (tetratricopeptide repeats) are those belonging to the steroid receptor-Hsp90 heterocomplex. The TPR domain immunophilins FKBP51 and FKBP52 are the best characterized due to their ability to regulate both the subcellular location of glucocorticoid receptor (GR) and its transcriptional activity. In this study, our objective was to analyse the effects of other TPR proteins such as PP5, SGT1α and 14-3-3σ on the regulation of androgen receptor (AR) and GR. The overexpression of PP5 favored the nuclear retention of GR, while the overexpression of SGT1α did not affect the subcellular distribution of the receptor. In contrast, the overexpression of 14-3-3σ delayed the GR nuclear import and accelerated its nuclear export. This effect is similar to the overexpression of the isolated TPR domain. Co-immunoprecipitation assays showed that 14-3- 3σ is part of the complexes of GR, but not SGT1α, suggesting that 14-3-3σ could displace efficiently FKBP52-dynein from the GR-Hsp90 complex. None of the three TPR proteins affected the AR nuclear import rate. However, the transcriptional activity of both receptors was inhibited by SGT1α, despite having no effect on the subcellular distribution thereof. Interestingly, PP5 and 14-3-3σ showed a biphasic response in the GR transcriptional activity, i.e., a slight increase in expression stimulates transcription, but it is inhibited with higher levels. On the other hand, we observed that PP5 was able to stimulate the activity of AR, while 14-3-3σ and SGT1α showed an inhibitory effect. These observations suggest that the balance of expression of these TPR proteins affect the biological activity of both AR and GR, which could be relevant in processes commanded by the relative activity balance of both receptors.