The androgen receptor (AR), a nuclear transcription factor, mediates male sexual differentiation, and its excessive action is associated with prostate cancer. We have characterized a negative regulatory domain in the AR hinge region, which interacted with filamin A (FLNa), an actin-binding cytoskeletal protein. FLNa interfered with AR interdomain interactions and competed with the coactivator transcriptional intermediary factor 2 to specifically down-regulate AR function. Although full-length FLNa was predominantly cytoplasmic, a C-terminal 100-kDa fragment of FLNa colocalized with AR to the nucleus. This naturally occurring FLNa fragment repressed AR transactivation and disrupted AR interdomain interactions and transcriptional intermediary factor 2-activated AR function in a manner reminiscent of full-length FLNa, raising the possibility that the inhibitory effects of cytoplasmic FLNa may be transduced through this fragment, which can localize to the nucleus and form part of the pre-initiation complex. This unanticipated role of FLNa adds to the growing evidence for the involvement of cytoskeletal proteins in transcription regulation. T he androgen receptor (AR), a member of the steroid͞ nuclear receptor superfamily, mediates male morphogenesis in utero, gametogenesis and prostate growth at puberty, and the development of prostatic cancer in older men. The AR has four principal domains: a large N-terminal transactivation domain (ARTAD), a DNA-binding domain (ARDBD), and a hinge domain, followed by the C-terminal ligand-binding domain (ARLBD). In the absence of androgen, it is generally accepted that AR is cytoplasmic. Androgens bind specifically to a ligandbinding pocket in the lower half of the LBD, causing a conformation change (1), the release of heat-shock proteins, and translocation of the ligand-AR complex to the nucleus, where the DBD interacts with specific response elements on the promoters of target genes. Transactivation functions reside mainly in the ARTAD, and very minimal activity can be demonstrated in the ARLBD (2, 3). Unlike other steroid receptors, transactivity depends on ligand-induced interactions between the ARTAD and ARLBD, and mutations that reduce TAD-LBD interactions affect AR activity, causing androgen insensitivity syndromes (4-6). Like other transcription regulators, the promoter-bound AR serves as a nidus to recruit cofactors that up-regulate (coactivators) or down-regulate (corepressors) AR activity. The most clearly defined class of coactivators is the p160͞steroid receptor coactivator (SRC) family. They include SRC1, transcriptional intermediary factor 2 (SRC2͞TIF2), and SRC3͞TRAM1͞A IB1͞pCIP͞ACTR͞ RAC3, who bind hydrophobic grooves in the LBDs of steroid receptors via LXXLL motifs in their nuclear-receptorinteracting boxes, draw in cAMP-response element-binding protein (CBP͞p300), pCAF, and other cofactors to modulate chromatin and initiate transcription by RNA polymerase II (7). Of the p160͞SRC proteins, TIF2 interacts most strongly with the AR (8) and, in concert with CBP͞p30...
Androgens are critical steroid hormones that determine the expression of the male phenotype. Their actions are mediated by a single androgen receptor (AR) which, upon ligand binding, translocates to the nucleus to regulate the expression of androgen-responsive genes. Mutations that disrupt AR function totally result in the complete feminization of 46 XY individuals and the complete androgen insensitivity syndrome. Studies have revealed that AR mutations that do not lead to complete abrogation of its activity can cause a wide spectrum of milder androgen insensitivity syndromes, from ambiguous genitalia in newborn infants to 'idiopathic' male infertility. Recent studies indicate that missense amino-acid substitutions in the ligand-binding domain of the AR result in infertility through a novel mechanism that involves defective protein-protein interactions between receptor domains and coactivator proteins. Independent of missense mutations, studies involving Singaporean, Australian, North American and Japanese subjects indicate that increases in length of a trinucleotide repeat (CAG) tract, encoding a polyglutamine stretch in the transactivation domain of the AR, are associated with increased risk of defective spermatogenesis and undermasculinization. This association was however not observed in European populations, suggesting that the genetic background may play a significant role in the expression of the AR defects.
Normal spermatogenesis depends on a sequential cascade of genetic events triggered by factors encoded by sex chromosomes. To determine the contribution of genetic aberrations to male infertility, the X-linked androgen receptor (AR) gene was examined for mutations and polymorphisms in a large cohort of infertile men. Genetic screening of over 400 patients and controls showed that defects in the AR gene lead to the production of dysfunctional receptor protein in up to 10% of males with abnormally low sperm production and male infertility. The dozens of mutations and polymorphisms uncovered were associated with subtly reduced intrinsic AR activity, and are of two main categories: polymorphic changes in length of a trinucleotide CAG tract in the N-terminal transactivation domain, and missense mutations in the C-terminal ligand-binding domain. These polymorphisms and mutations are associated with reduced AR function due to defective intermolecular protein-protein interactions with coactivator molecules. Genetic screening for AR mutations and polymorphism should be offered to severely oligospermic and azoospermic patients. These traits can be transmitted to progeny, and counseling can be offered to affected families. Clarification of the molecular mechanisms of pathogenesis has led to rational hormonal therapy.
Sex-typical body shapes (a man's muscular physique and a woman's hourglass figure) are an outcome of evolutionary adaptation in reproductive fitness because they convey information about gene quality, health and fertility, which are important elements for mate selection. Therefore, sex-typical body shape should be linked to other known physical attributes related to reproductive success. The purpose of this study was to investigate the relationships between sex-typical body shape and morphological traits that signal quality [fluctuating asymmetry (FA), hand grip strength (HGS), digit ratios (2D:4D) and leg-to-torso ratio (LTR)] and their role in reproductive fitness. The relationships among quality indicators were also examined. The results revealed that low FA, high HGS, high LTR, and interaction of FA with right 2D:4D predicted men's masculine body shape. Females with a more feminine body shape had low HGS, high right 2D:4D, and low LTR compared to those with more masculine body shape. Among quality indicators, no significant relationships were found in both males and females. Moreover, men with more wedge-shaped bodies showed earlier sexual maturation and had more sexual opportunities, whereas such effects were not observed in women. These findings support the evolutionary hypothesis that sex-typical body shape is a reliable signal of health and fertility and a consequence of sexual selection based on genetic and phenotypic quality.
Background: This study investigated whether pre-and peri-disaster experiences influence on Post-Traumatic Stress Disorder (PTSD) and whether post-disaster stress by life changes have impact on PTSD after controlling pre-and peri-disaster factors. Methods: Data came from a sample of 1,182 respondents who experienced natural disasters (flood and typhoon) in South Korea from 2012 to 2015. The SPSS Win 22.0 program was used for descriptive analysis, t-test, Chi-square test, Pearson's correlation and logistic regression analysis. Results: The results indicated that 24.3% of the disaster victims were in PTSD risk group. Compared with non-PTSD, PTSD risk group showed lower interpersonal trust and satisfaction, higher depression and anxiety, and lower subjective well-being. The results of hierarchical logistc regression revealed that all pre-, peri-, and post-disaster factors increased the probability of developing PTSD, except for relocation of residence. Moreover, a primary post-disaster predictor of PTSD was economic distress after controlling for pre-and peri-disaster. Conclusions: This study tested relative contributions of post-disaster factors on PTSD.
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