Pax6 Represses Androgen Receptor-Mediated Transactivation by Inhibiting Recruitment of the Coactivator SPBP

The androgen receptor (AR) has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer

Modulation of Brain β-Endorphin Concentration by the Specific Part of the Y Chromosome in Mice

International audienceBackground: Several studies in animal models suggest a possible effect of the specific part of the Y-chromosome (Y NPAR) on brain opioid, and more specifically on brain b-endorphin (BE). In humans, male prevalence is found in autistic disorder in which observation of abnormal peripheral or central BE levels are also reported. This suggests gender differences in BE associated with genetic factors and more precisely with Y NPAR. Methodology/Principal Findings: Brain BE levels and plasma testosterone concentrations were measured in two highly inbred strains of mice, NZB/BlNJ (N) and CBA/HGnc (H), and their consomic strains for the Y NPAR. An indirect effect of the Y NPAR on brain BE level via plasma testosterone was also tested by studying the correlation between brain BE concentration and plasma testosterone concentration in eleven highly inbred strains. There was a significant and major effect (P,0.0001) of the Y NPAR in interaction with the genetic background on brain BE levels. Effect size calculated using Cohen's procedure was large (56% of the total variance). The variations of BE levels were not correlated with plasma testosterone which was also dependent of the Y NPAR. Conclusions/Significance: The contribution of Y NPAR on brain BE concentration in interaction with the genetic background is the first demonstration of Y-chromosome mediated control of brain opioid. Given that none of the genes encompassed by the Y NPAR encodes for BE or its precursor, our results suggest a contribution of the sex-determining region (Sry, carried by Y NPAR) to brain BE concentration. Indeed, the transcription of the Melanocortin 2 receptor gene (Mc2R gene, identified as the proopiomelanocortin receptor gene) depends on the presence of Sry and BE is derived directly from proopiomelanocortin. The results shed light on the sex dependent differences in brain functioning and the role of Sry in the BE system might be related to the higher frequency of autistic disorder in males

Organizing Effects of Sex Steroids on Brain Aromatase Activity in Quail

Preoptic/hypothalamic aromatase activity (AA) is sexually differentiated in birds and mammals but the mechanisms controlling this sex difference remain unclear. We determined here (1) brain sites where AA is sexually differentiated and (2) whether this sex difference results from organizing effects of estrogens during ontogeny or activating effects of testosterone in adulthood. In the first experiment we measured AA in brain regions micropunched in adult male and female Japanese quail utilizing the novel strategy of basing the microdissections on the distribution of aromatase-immunoreactive cells. The largest sex difference was found in the medial bed nucleus of the stria terminalis (mBST) followed by the medial preoptic nucleus (POM) and the tuberal hypothalamic region. A second experiment tested the effect of embryonic treatments known to sex-reverse male copulatory behavior (i.e., estradiol benzoate [EB] or the aromatase inhibitor, Vorozole) on brain AA in gonadectomized adult males and females chronically treated as adults with testosterone. Embryonic EB demasculinized male copulatory behavior, while vorozole blocked demasculinization of behavior in females as previously demonstrated in birds. Interestingly, these treatments did not affect a measure of appetitive sexual behavior. In parallel, embryonic vorozole increased, while EB decreased AA in pooled POM and mBST, but the same effect was observed in both sexes. Together, these data indicate that the early action of estrogens demasculinizes AA. However, this organizational action of estrogens on AA does not explain the behavioral sex difference in copulatory behavior since AA is similar in testosterone-treated males and females that were or were not exposed to embryonic treatments with estrogens