<div>Abstract<p>The androgen receptor (AR) plays a key role in progression to incurable androgen ablation–resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand-binding domain (designated as AR3, AR4, and AR5) in hormone-insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active, and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly up-regulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells, whereas specific knockdown of AR3 expression (without altering AR level) in hormone-resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct, yet essential, role in ablation-independent growth through the regulation of a unique set of genes, including <i>AKT1</i>, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation independence during PCA progression, and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. [Cancer Res 2009;69(6):2305–13]</p></div>
The influence of social and family factors on adolescent mental health has been widely valued. Considering adolescents' family systems in a broader social context facilitates a better understanding of their mental health, which also has special significance in the post-epidemic era. The purpose of the present study was to explore the relationship between social support and family functioning during adolescence. Students from two middle schools in Fujian province, China, were recruited as participants. Seven hundred and fifty-four participants completed the questionnaire twice in six-month intervals. We constructed a cross-lagged model by using IBM SPSS AMOS 26.0 to test the relationship between these two variables. Social support and family functioning predicted each other in the girls, but not for the boys' sample. The results of this study suggested that the interaction between family and social factors and the possible gender differences should be considered when dealing with adolescents' mental health problems.
<p>Please note the Supplementary Methods were corrected by the authors and re-posted on March 16, 2009. The corrected file provides an updated GEO accession number. The original and revised versions are provided for reference.</p>
Objective To investigate the expressions of androgen receptor (AR) and transforming growth factor β receptor Ⅰ (TGF β RI) in benign prostatic hyperplasia (BPH). Methods AR and TGF β RI expressions were detected in 31 human prostatic hyperplasia tissue specimens and in 22 normal prostatic tissues as controls. Results Positive expressions of AR and TGF β RI were much higher in the epithelial and mysenchymal of BPH than those in normal prostatic tissue ( P 0.05) and expression of AR was signigicantly associated with that of TGF β RI in stromal tissue of BPH ( r =0.358, P 0.05). Conclusions Expressions of AR and TGF β RI might play a role in the regulation of the growth of prostatic tissue and therefore might be a causative factor in prostatic hyperplasia.
Androgen receptor (AR) mediates transcriptional activation of diverse target genes through interactions with various coactivators that may alter its function and help mediate the switch between prostate cell proliferation and differentiation. We recently identified p44/MEP50 as an AR coactivator and further showed that it is expressed primarily in the nucleus and cytoplasm of benign prostate epithelial and prostate cancer cells, respectively. We also showed that haploinsufficiency in p44 +/− mice causes prostate epithelial cell proliferation. To establish direct cause-and-effect relationships, we have used p44 fusion proteins that are selectively expressed in the nucleus or cytoplasm of prostate cancer cells (LNCaP), along with RNAi analyses, to examine effects of p44 both in vitro and in vivo (in tumor xenografts). We show that preferential expression of p44 in the nucleus inhibits proliferation of LNCaP cells in an AR-dependent manner, whereas preferential expression of p44 in the cytoplasm enhances cell proliferation. These effects appear to be mediated, at least in part, through the regulation of distinct cell-cycle regulatory genes that include p21 (up-regulated by nuclear p44) and cyclin D2 and CDK6 (up-regulated by cytoplasmic p44). Importantly, we also demonstrate that altered p44 expression is associated with androgen-independent prostate cancer. Our results indicate that nuclear p44 and cytoplasmic p44 have distinct and opposing functions in the regulation of prostate cancer cell proliferation.
<div>Abstract<p>The androgen receptor (AR) plays a key role in progression to incurable androgen ablation–resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand-binding domain (designated as AR3, AR4, and AR5) in hormone-insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active, and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly up-regulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells, whereas specific knockdown of AR3 expression (without altering AR level) in hormone-resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct, yet essential, role in ablation-independent growth through the regulation of a unique set of genes, including <i>AKT1</i>, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation independence during PCA progression, and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. [Cancer Res 2009;69(6):2305–13]</p></div>
Supplementary Figures 1-2 from Tyrosine Kinase Etk/BMX Is Up-regulated in Human Prostate Cancer and Its Overexpression Induces Prostate Intraepithelial Neoplasia in Mouse
Supplementary Figures 1-20, Table 1 from A Novel Androgen Receptor Splice Variant Is Up-regulated during Prostate Cancer Progression and Promotes Androgen Depletion–Resistant Growth
The SMPD4 gene encodes sphingomyelin phosphodiesterase 4, which preferentially hydrolyzes sphingomyelin over other phospholipids. The biallelic loss-of-function variants of SMPD4 have been identified in a group of children with neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA). Here, we report a girl of Chinese ancestry with intrauterine growth restriction, microcephaly, postnatal developmental delay, arthrogryposis, hypertonicity, seizure, and hypomyelination on brain magnetic resonance imaging; biallelic null variants (c.1347C > G [p.Tyr449*]; Chr2 [GRCh37]: g.130877574_131221737del [whole-gene deletion]) were detected by whole-exome sequencing. Our case is the first report of NEDMABA of Chinese ancestry, confirming the involvement of SMPD4 in NEDMABA and expanding the mutation spectrum of this syndrome.
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