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1
Brayman, Melissa J., Patricia A. Pepa, Sara E. Berdy, and Pamela L. Mellon. "Androgen Receptor Repression of GnRH Gene Transcription." Molecular Endocrinology 26, no. 1 (January 1, 2012): 2–13. http://dx.doi.org/10.1210/me.2011-1015.
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Abstract Alterations in androgen levels lead to reproductive defects in both males and females, including hypogonadotropic hypogonadism, anovulation, and infertility. Androgens have been shown to down-regulate GnRH mRNA levels through an androgen receptor (AR)-dependent mechanism. Here, we investigate how androgen regulates expression from the GnRH regulatory region in the GT1-7 cell line, a model of GnRH neurons. A synthetic androgen, R1881, repressed transcription from the GnRH promoter (GnRH-P) in an AR-dependent manner, and liganded AR associated with the chromatin at the GnRH-P in live GT1-7 cells. The three known octamer-binding transcription factor-1 (Oct-1) binding sites in GnRH-P were required for AR-mediated repression, although other sequences were also involved. Although a multimer of the consensus Oct-1 binding site was not repressed, a multimer of the cluster of Oct-1, Pre-B cell leukemia transcription factor (Pbx)/Prep, and NK2 homeobox 1 (Nkx2.1) binding sites, found at −106/−91 in GnRH-P, was sufficient for repression. In fact, overexpression of any of these factors disrupted the androgen response, indicating that a balance of factors in this tripartite complex is required for AR repression. AR bound to this region in EMSA, indicating a direct interaction of AR with DNA or with other transcription factors bound to GnRH-P at this sequence. Collectively, our data demonstrate that GnRH transcription is repressed by AR via multiple sequences in GnRH-P, including three Oct-1 binding sites, and that this repression requires the complex interaction of several transcription factors.
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Ilaslan, Erkut, Renata Markosyan, Patrick Sproll, Brian J. Stevenson, Malgorzata Sajek, Marcin P. Sajek, Hasmik Hayrapetyan, et al. "The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome." International Journal of Molecular Sciences 21, no. 21 (November 9, 2020): 8403. http://dx.doi.org/10.3390/ijms21218403.
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Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.
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Holycross, Bethany J., Monica Kukielka, Yoshinori Nishijima, Ruth A. Altschuld, Cynthia A. Carnes, and George E. Billman. "Exercise training normalizes β-adrenoceptor expression in dogs susceptible to ventricular fibrillation." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 5 (November 2007): H2702—H2709. http://dx.doi.org/10.1152/ajpheart.00763.2007.
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Previous studies demonstrated an enhanced β2-adrenoceptor (AR) responsiveness in animals susceptible to ventricular fibrillation (VF) that was eliminated by exercise training. The present study investigated the effects of endurance exercise training on β1-AR and β2-AR expression in dogs susceptible to VF. Myocardial ischemia was induced by a 2-min occlusion of the left circumflex artery during the last minute of exercise in dogs with healed infarctions: 20 had VF [susceptible (S)] and 13 did not [resistant (R)]. These dogs were randomly assigned to either 10-wk exercise training [treadmill running; n = 9 (S) or 8 (R)] or an equivalent sedentary period [ n = 11 (S) or 5 (R)]. Left ventricular tissue β-AR protein and mRNA were quantified by Western blot analysis and RT-PCR, respectively. Because β2-ARs are located in caveolae, caveolin-3 was also quantified. β1-AR gene expression decreased (∼5-fold), β2-AR gene expression was not changed, and the ratio of β2-AR to β1-AR gene expression was significantly increased in susceptible compared with resistant dogs. β1-AR protein decreased (∼50%) and β2-AR protein increased (400%) in noncaveolar fractions of the cell membrane in susceptible dogs. Exercise training returned β1-AR gene expression to levels seen in resistant animals but did not alter β2-AR protein levels in susceptible dogs. These data suggest that β1-AR gene expression was decreased in susceptible dogs compared with resistant dogs and, further, that exercise training improves β1-AR gene expression, thereby restoring a more normal β-AR balance.
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Daniel, Mark, Todd P. Knutson, Jamie M. Sperger, Yingming Li, Anupama Singh, Charlotte N. Stahlfeld, Courtney Passow, Benjamin Auch, Joshua M. Lang, and Scott M. Dehm. "AR gene rearrangement analysis in liquid biopsies reveals heterogeneity in lethal prostate cancer." Endocrine-Related Cancer 28, no. 9 (September 1, 2021): 645–55. http://dx.doi.org/10.1530/erc-21-0157.
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Castration-resistant prostate cancer (CRPC) is driven by AR gene aberrations that arise during androgen receptor (AR)-targeted therapy. AR amplification and mutations have been profiled in circulating tumor cells (CTCs), but whether AR gene rearrangements can be assessed in CTCs is unknown. In this study, we leveraged CRPC cell lines with defined AR gene rearrangements to develop and validate a CTC DNA analysis approach that utilized whole genome amplification and targeted DNA-sequencing of AR and other genes important in CRPC. We tested the utility of this approach by analyzing matched CTC DNA and plasma cell-free DNA (cfDNA) from a case series of ten CRPC patients. One of ten CTC samples and two of ten cfDNA samples were positive for AR gene rearrangements. All AR gene rearrangements were discordant between matched liquid biopsy samples. One patient harbored separate AR gene rearrangements in CTC DNA and cfDNA, but concordant AR amplification and AR T878A mutation. This patient also displayed concordant loss of TP53 and PTEN, but the loss of RB1 in cfDNA only. The overall frequency of discordant alterations in these genes between matched CTC DNA and cfDNA was high. This study establishes the technical feasibility of analyzing structural rearrangements, mutations, and copy number variants in AR and other CRPC genes using two different sources of DNA from a single blood sample. Paired CTC DNA and cfDNA analysis may have utility for capturing the heterogeneity of genetic alterations in CRPC patients.
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Xavier, Basil Britto, Anupam J. Das, Guy Cochrane, Sandra De Ganck, Samir Kumar-Singh, Frank Møller Aarestrup, Herman Goossens, and Surbhi Malhotra-Kumar. "Consolidating and Exploring Antibiotic Resistance Gene Data Resources." Journal of Clinical Microbiology 54, no. 4 (January 27, 2016): 851–59. http://dx.doi.org/10.1128/jcm.02717-15.
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The unrestricted use of antibiotics has resulted in rapid acquisition of antibiotic resistance (AR) and spread of multidrug-resistant (MDR) bacterial pathogens. With the advent of next-generation sequencing technologies and their application in understanding MDR pathogen dynamics, it has become imperative to unify AR gene data resources for easy accessibility for researchers. However, due to the absence of a centralized platform for AR gene resources, availability, consistency, and accuracy of information vary considerably across different databases. In this article, we explore existing AR gene data resources in order to make them more visible to the clinical microbiology community, to identify their limitations, and to propose potential solutions.
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Agoulnik, Irina U., William E. Bingman, Manjula Nakka, Wei Li, Qianben Wang, X. Shirley Liu, Myles Brown, and Nancy L. Nancy L. "Target Gene-Specific Regulation of Androgen Receptor Activity by p42/p44 Mitogen-Activated Protein Kinase." Molecular Endocrinology 22, no. 11 (November 1, 2008): 2420–32. http://dx.doi.org/10.1210/me.2007-0481.
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Abstract Evidence that the androgen receptor (AR) is not only important in androgen-dependent prostate cancer, but also continues to play a role in tumors that become resistant to androgen deprivation therapies, highlights the need to find alternate means to block AR activity. AR, a hormone-activated transcription factor, and its coactivators are phosphoproteins. Thus, we sought to determine whether inhibition of specific cell signaling pathways would reduce AR function. We found that short-term inhibition of p42/p44 MAPK activity either by a MAPK kinase inhibitor, U0126, or by depletion of kinase with small interfering RNA caused target gene-specific reductions in AR activity. AR enhances histone H3 acetylation of target genes that are sensitive to U0126 including prostate-specific antigen and TMPRSS2, but does not increase histone H3 acetylation of the U0126-resistant PMEPA1 gene. Thus, although AR induces transcription of many target genes, the molecular changes induced by AR at the chromatin level are target gene specific. Long-term treatment (24–48 h) with U0126 causes a G1 cell cycle arrest and reduces AR expression both through a decrease in AR mRNA and a reduction in AR protein stability. Thus, treatments that reduce p42/p44 MAPK activity in prostate cancer have the potential to reduce AR activity through a reduction in expression levels as well as by target gene-selective inhibition of AR function.
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Shiota, Masaki, Akira Yokomizo, and Seiji Naito. "Increased androgen receptor transcription: a cause of castration-resistant prostate cancer and a possible therapeutic target." Journal of Molecular Endocrinology 47, no. 1 (April 19, 2011): R25—R41. http://dx.doi.org/10.1530/jme-11-0018.
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Few effective therapies exist for the treatment of castration-resistant prostate cancer (CRPC). Recent evidence suggests that CRPC may be caused by augmented androgen/androgen receptor (AR) signaling, generally involving AR overexpression. Aberrant androgen/AR signaling associated with AR overexpression also plays a key role in prostate carcinogenesis. Although AR overexpression could be attributed to gene amplification, only 10–20% of CRPCs exhibit AR gene amplification, and aberrant AR expression in the remaining instances of CRPC is thought to be attributed to transcriptional, translational, and post-translational mechanisms. Overexpression of AR at the protein level, as well as the mRNA level, has been found in CRPC, suggesting a key role for transcriptional regulation of AR expression. Since the analysis of the AR promoter region in the 1990s, several transcription factors have been reported to regulate AR transcription. In this review, we discuss the molecules involved in the control of AR gene expression, with emphasis on its transcriptional control by transcription factors in prostate cancer. We also consider the therapeutic potential of targeting AR expression.
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Xia, Tingting, Hongru Sun, Hao Huang, Haoran Bi, Rui Pu, Lei Zhang, Yuanyuan Zhang, et al. "Androgen receptor gene methylation related to colorectal cancer risk." Endocrine Connections 8, no. 7 (July 2019): 979–87. http://dx.doi.org/10.1530/ec-19-0122.
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According to its incidence patterns, colorectal cancer (CRC) tends to occur more frequently in males than in females, and the evidence shows that CRC is a hormone-related tumor. These findings indicate that androgen receptor (AR) gene methylation might be important for the regulation of the CRC risk in the different sexes. We used a case–control study to investigate the association between AR methylation in peripheral blood (PBL) and CRC risk. A cohort study was conducted to analyze the effect of AR methylation levels in both PBL and tissue on the prognosis of CRC. AR methylation levels were detected using methylation-sensitive high-resolution melting (MS-HRM). The results indicate that the hypomethylation of AR was significantly associated with the risk of CRC (OR = 1.869, 95% CI: 1.629–2.141, P < 0.001), and the results remained similar after adjusting for the propensity score (PS) (OR = 1.344, 95% CI: 1.147–1.575, P < 0.001) and PS matching (OR = 1.138, 95% CI: 1.000–1.292 P = 0.049). The hypomethylation of AR was significantly associated with CRC in males (OR = 2.309, 95% CI: 1.200–4.245; P = 0.012) but not females (OR = 1.000, 95% CI: 0.567–1.765; P = 0.999). The methylation status of AR in PBL and tissue does not seem to be associated with prognosis in colorectal cancer (OR = 1.425, 95% CI: 0.895–2.269, P = 0.135; OR = 0.930, 95% CI: 0.674–1.285, P = 0.661). We conclude that AR hypomethylation in PBL is associated with a high risk of CRC and may serve as a biomarker. Further studies involving large sample sizes are needed to validate the results of this study.
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Rossi, R., P. Franceschetti, I. Maestri, E. Magri, L. Cavazzini, E. C. degli Uberti, and L. del Senno. "Evidence for androgen receptor gene expression in human thyroid cells and tumours." Journal of Endocrinology 148, no. 1 (January 1996): 77–85. http://dx.doi.org/10.1677/joe.0.1480077.
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Abstract Androgen-binding activity has been identified in normal and pathological thyroids, but evidence for the expression of the canonic androgen receptor (AR) in the thyroid has not been provided so far. In this study we have used reverse transcription (RT)-PCR to examine RNA expression of the canonic AR gene in human thyroid tissues, in primary cultures of human thyrocytes and in a variety of neoplastic thyroid cell lines (NPA, TPC and WRO). An AR cDNA fragment with the expected size of 262 bp was detected in normal tissues and cultured thyrocytes as well as in neoplastic cell lines, demonstrating that the gene for AR is indeed expressed in thyroid follicular cells. Immunocytochemical analysis revealed the presence of the AR protein in cancer cell lines and androgen treatment increased nuclear positivity to AR. In a survey of 35 thyroid tissues AR cDNA was detected in all the non-neoplastic samples (6 normal and 3 goitrous) and in 19 of 26 neoplastic samples. AR cDNA was not detected in 4 of the 9 follicular adenomas and in 3 of the 12 papillary carcinomas. AR was revealed by immunohistochemistry in 1 of 2 normal thyroids, in 1 goiter and in 1 of 2 neoplastic thyroids. These findings show the presence of the canonic AR in the human thyroid. Journal of Endocrinology (1996) 148, 77–85
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Zhang, Lu, Ying Huang, Yang Zhou, Timothy Buckley, and Hua H. Wang. "Antibiotic Administration Routes Significantly Influence the Levels of Antibiotic Resistance in Gut Microbiota." Antimicrobial Agents and Chemotherapy 57, no. 8 (May 20, 2013): 3659–66. http://dx.doi.org/10.1128/aac.00670-13.
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ABSTRACTThis study examined the impact of oral exposure to antibiotic-resistant bacteria and antibiotic administration methods on antibiotic resistance (AR) gene pools and the profile of resistant bacteria in host gastrointestinal (GI) tracts using C57BL/6J mice with natural gut microbiota. Mice inoculated with a mixture oftet(M)-carryingEnterococcusspp. orblaCMY-2-carryingEscherichia coliwere treated with different doses of tetracycline hydrochloride (Tet) or ampicillin sodium (Amp) and delivered via either feed or intravenous (i.v.) injection. Quantitative PCR assessment of mouse fecal samples revealed that (i) AR gene pools were below the detection limit in mice without prior inoculation of AR gene carriers regardless of subsequent exposure to corresponding antibiotics; (ii) oral exposure to high doses of Tet and Amp in mice inoculated with AR gene carriers led to rapid enrichment of corresponding AR gene pools in feces; (iii) significantly less or delayed development of AR in the GI tract of the AR carrier-inoculated mice was observed when the same doses of antibiotics were administered via i.v. injection rather than oral administration; and (iv) antibiotic dosage, and maybe the excretion route, affected AR in the GI tract. The shift of dominant AR bacterial populations in the gut microbiota was consistent with the dynamics of AR gene pools. The emergence of endogenous resistant bacteria in the gut microbiota corresponding to drug exposure was also observed. Together, these data suggest that oral administration of antibiotics has a prominent effect on AR amplification and development in gut microbiota, which may be minimized by alternative drug administration approaches, as illustrated by i.v. injection in this study and proper drug selection.
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Yang, Jun, Lin-Wang Dong, Chaoshu Tang, and Maw-Shung Liu. "Transcriptional and posttranscriptional regulation of β2-adrenergic receptor gene in rat liver during sepsis." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 277, no. 1 (July 1, 1999): R132—R139. http://dx.doi.org/10.1152/ajpregu.1999.277.1.r132.
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Changes in β2-adrenergic receptor (β2-AR) gene expression in the rat liver during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Septic rats exhibit two metabolically distinct phases: an initial hyperglycemic (9 h after CLP; early sepsis) followed by a hypoglycemic phase (18 h after CLP; late sepsis). The [3H]dihydroalprenolol binding studies show that the density of β2-AR was decreased by 12 and 35% during the early and late phases of sepsis, respectively. Western blot analyses depict that the β2-AR protein level was reduced by 37 and 72% during early and late sepsis, respectively. The reverse transcription polymerase chain reaction and Southern blot analyses reveal that the steady-state level of β2-AR mRNA was decreased by 37% during early phase and 77% during late phase of sepsis. Nuclear run-off assays show that the rate of transcription of β2-AR mRNA was reduced by 36% during early sepsis and 64% during late sepsis. The stability assays indicate that the half-life of β2-AR mRNA was shortened by 21 and 50% during the early and late phases of sepsis, respectively, indicating that the rate of degradation of β2-AR mRNA was progressively enhanced during sepsis. These findings demonstrate that the β2-AR gene was underexpressed in the liver during the progression of sepsis, and, furthermore, the underexpression of the β2-AR gene was the result of a reduction in the rate of transcription coupled with an enhancement in the rate of degradation of β2-AR gene transcripts. Thus our findings that the transcriptional and posttranscriptional regulation of β2-AR gene associated with decreases in β2-AR number and its protein expression may provide a molecular mechanistic explanation for the development of hypoglycemia during the late stage of sepsis.
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Dong, Xuesen, Joan Sweet, John R. G. Challis, Theodore Brown, and Stephen J. Lye. "Transcriptional Activity of Androgen Receptor Is Modulated by Two RNA Splicing Factors, PSF and p54nrb." Molecular and Cellular Biology 27, no. 13 (April 23, 2007): 4863–75. http://dx.doi.org/10.1128/mcb.02144-06.
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ABSTRACT Nuclear receptors regulate gene activation or repression through dynamic interactions with coregulators. The interactions between nuclear receptors and RNA splicing factors link gene transcription initiation with pre-mRNA splicing, providing a coordinated control of the products of gene transcription. Here we report that two RNA splicing factors, PTB-associated splicing factor (PSF) and p54nrb, synergistically form protein complexes with the androgen receptor (AR) in a ligand-independent manner and inhibit its transcriptional activity. PSF does not affect AR protein stability, as in the case of the progesterone receptor, but impedes the interaction of AR with the androgen response element. Both splicing factors interact directly with mSin3A and attract mSin3A to the AR complex in a synergistic manner. The suppression of AR transcriptional activity by PSF and p54nrb is reversed by the inhibition of histone deacetylase activity. These data demonstrated that PSF and p54nrb complex with AR and play a key role in modulating AR-mediated gene transcription.
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Jia, Li, Howard C. Shen, Marcus Wantroba, Omar Khalid, Gangning Liang, Qingcai Wang, Elisabet Gentzschein, et al. "Locus-Wide Chromatin Remodeling and Enhanced Androgen Receptor-Mediated Transcription in Recurrent Prostate Tumor Cells." Molecular and Cellular Biology 26, no. 19 (October 1, 2006): 7331–41. http://dx.doi.org/10.1128/mcb.00581-06.
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ABSTRACT Prostate cancers (PCas) become resistant to hormone withdrawal through increased androgen receptor (AR) signaling. Here we show increased AR-mediated transcription efficiency in PCa cells that have acquired the ability to grow in low concentrations of androgen. Compared to androgen-dependent PCa cells, these cells showed increased activity of transiently transfected reporters and increased mRNA synthesis relative to levels of AR occupancy of the prostate-specific antigen (PSA) gene. The locus also displayed up to 10-fold-higher levels of histone H3-K9/K14 acetylation and H3-K4 methylation across the entire body of the gene. Although similar increased mRNA expression and locus-wide histone acetylation were also observed at another kallikrein locus (KLK2), at a third AR target locus (TMPRSS2) increased gene expression and locus-wide histone acetylation were not seen in the absence of ligand. Androgen-independent PCa cells have thus evolved three distinctive alterations in AR-mediated transcription. First, increased RNA polymerase initiation and processivity contributed to increased gene expression. Second, AR signaling was more sensitive to ligand. Third, locus-wide chromatin remodeling conducive to the increased gene expression in the absence of ligand was apparent and depended on sustained AR activity. Therefore, increased AR ligand sensitivity as well as locus-specific chromatin alterations contribute to basal gene expression of a subpopulation of specific AR target genes in androgen-independent PCa cells. These features contribute to the androgen-independent phenotype of these cells.
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Yeap, Bu B., Romano G. Krueger, and Peter J. Leedman. "Differential Posttranscriptional Regulation of Androgen Receptor Gene Expression by Androgen in Prostate and Breast Cancer Cells*." Endocrinology 140, no. 7 (July 1, 1999): 3282–91. http://dx.doi.org/10.1210/endo.140.7.6769.
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Abstract Androgens, via the androgen receptor (AR), modulate the growth and proliferation of prostate and breast cancer cells. However, the molecular mechanisms underlying the regulation of AR gene expression by androgen in these cells remain to be fully elucidated. To explore differences in AR gene expression between these hormone-responsive tumor cell types, we studied androgen-responsive LNCaP prostate cancer and AR positive MDA453 breast cancer cells. Dihydrotestosterone (DHT) 10 nm increased LNCaP cell proliferation and the proportion of LNCaP cells in S-phase of the cell cycle but inhibited MDA453 cell proliferation and reduced the proportion of MDA453 cells in S-phase of cell cycle. In both these cell lines, DHT decreased total AR messenger RNA (mRNA) but increased AR protein. In LNCaP cells, DHT down-regulated AR mRNA transcription but stabilized AR mRNA. In contrast, in MDA453 cells, DHT had no effect on AR mRNA transcription but destabilized AR mRNA. In summary, transcriptional down-regulation induced by androgens in LNCaP cells results in down-regulation of steady-state AR mRNA despite an androgen-induced increase in AR mRNA stability. However, in MDA453 cells, posttranscriptional destabilization of AR mRNA appears to be the predominant mechanism resulting in down-regulation of AR mRNA by androgen. These results demonstrate cell-specific and divergent regulation of AR mRNA turnover by androgen and identify a novel pathway of androgen-induced posttranscriptional destabilization and down-regulation of AR mRNA in human breast cancer cells. Furthermore, these data establish an important role for posttranscriptional pathways in the regulation of AR gene expression by androgen in human prostate and breast cancer cells.
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Bai, Suxia, and Elizabeth M. Wilson. "Epidermal Growth Factor-Dependent Phosphorylation and Ubiquitinylation of MAGE-11 Regulates Its Interaction with the Androgen Receptor." Molecular and Cellular Biology 28, no. 6 (January 22, 2008): 1947–63. http://dx.doi.org/10.1128/mcb.01672-07.
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ABSTRACT The androgen receptor (AR) is a ligand-activated transcription factor that interacts with coregulatory proteins during androgen-dependent gene regulation. Melanoma antigen gene protein 11 (MAGE-11) is an AR coregulator that specifically binds the AR NH2-terminal FXXLF motif and modulates the AR NH2- and carboxyl-terminal N/C interaction to increase AR transcriptional activity. Here we demonstrate that epidermal growth factor (EGF) signaling increases androgen-dependent AR transcriptional activity through the posttranslational modification of MAGE-11. EGF in the presence of dihydrotestosterone stabilizes the AR-MAGE complex through the site-specific phosphorylation of MAGE-11 at Thr-360 and ubiquitinylation at Lys-240 and Lys-245. The time-dependent EGF-induced increase in AR transcriptional activity by MAGE-11 is mediated through AR activation functions 1 and 2 in association with the increased turnover of AR and MAGE-11. The results reveal a dynamic mechanism whereby growth factor signaling increases AR transcriptional activity through the covalent modification of an AR-specific coregulatory protein. Sequence conservation of the MAGE-11 phosphorylation and ubiquitinylation sites throughout the MAGE gene family suggests common regulatory mechanisms for this group of cancer-testis antigens.
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Łysiak, M., M. Trybuła, A. Malmström, M. Mudaisi, C. Bratthäll, M. Strandeus, P. Milos, M. Hallbeck, and P. Söderkvist. "P13.03 Sex-specific influence of androgen receptor gene expression on survival of glioblastoma patients." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii33. http://dx.doi.org/10.1093/neuonc/noab180.113.
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Abstract BACKGROUND The mRNA and protein expression of androgen receptor (AR) are upregulated in glioblastoma (GBM) and studies show that use of AR antagonists leads to apoptosis of GBM cells in vitro and reduction of tumor volume in a mouse model. With increased prevalence of GBM among males, the role and genetic alterations of AR are worth investigating, especially taking into account the location of AR on chromosome X and possible sex differences associated with it. MATERIAL AND METHODS Copy number (CN) and mRNA expression of AR were tested with droplet digital PCR in 106 fresh frozen GBM samples (34 females and 72 males) collected at Linköping University Hospital. This cohort was also subjected to AR promoter methylation analysis, where 17 CpG sites were the target of pyrosequencing. Methylation levels were then correlated with mRNA gene expression, independently for each sex, using Pearson correlation coefficient. Gene expression of AR was also analyzed in The Cancer Genome Atlas cohort of primary IDH wild type GBM (135 females and 219 males) and association of AR expression and overall survival (OS) was tested with Kaplan-Meier log rank analysis after dichotomization by maximally selected rank statistics. RESULTS DNA amplifications, as well as deletions of the AR were detected, with a higher frequency of alterations found in females (26.4% vs. 8.3%). AR gene expression correlated with methylation levels of two CpG sites in females (chrX:67543271, chrX:67543762) and three different CpG sites in males (chrX:67543889, chrX:67543895, chrX:67543899). There was no difference in the AR expression between males and females in neither of the cohorts, but significantly higher AR expression was found in the classical subtype of GBM in TCGA. Survival analysis of the TCGA cohort revealed the opposite effect of AR expression on OS of males and females, with high AR expression correlating with shorter OS in females (13.6 vs.15.7 months, p=0.035) and longer OS in males (16.6 vs. 12.2 months, p=0.04). Additional gene set enrichment analysis of these samples showed that high AR expression was strongly correlated with DNA repair but only in the male group. CONCLUSION Our results show that high AR mRNA expression in GBM exhibits different effects on patients’ survival depending on their sex, despite common occurrence of high AR expression and CN changes in males and females. The reasons for potential protective influence of AR in males remain unclear and require further investigations.
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Bai, Suxia, Bin He, and Elizabeth M. Wilson. "Melanoma Antigen Gene Protein MAGE-11 Regulates Androgen Receptor Function by Modulating the Interdomain Interaction." Molecular and Cellular Biology 25, no. 4 (February 15, 2005): 1238–57. http://dx.doi.org/10.1128/mcb.25.4.1238-1257.2005.
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ABSTRACT Gene activation by steroid hormone receptors involves the recruitment of the steroid receptor coactivator (SRC)/p160 coactivator LXXLL motifs to activation function 2 (AF2) in the ligand binding domain. For the androgen receptor (AR), AF2 also serves as the interaction site for the AR NH2-terminal FXXLF motif in the androgen-dependent NH2-terminal and carboxyl-terminal (N/C) interaction. The relative importance of the AR AF2 site has been unclear, since the AR FXXLF motif interferes with coactivator recruitment by competitive inhibition of LXXLL motif binding. In this report, we identified the X chromosome-linked melanoma antigen gene product MAGE-11 as an AR coregulator that specifically binds the AR NH2-terminal FXXLF motif. Binding of MAGE-11 to the AR FXXLF α-helical region stabilizes the ligand-free AR and, in the presence of an agonist, increases exposure of AF2 to the recruitment and activation by the SRC/p160 coactivators. Intracellular association between AR and MAGE-11 is supported by their coimmunoprecipitation and colocalization in the absence and presence of hormone and by competitive inhibition of the N/C interaction. AR transactivation increases in response to MAGE-11 and the SRC/p160 coactivators through mechanisms that include but are not limited to the AF2 site. MAGE-11 is expressed in androgen-dependent tissues and in prostate cancer cell lines. The results suggest MAGE-11 is a unique AR coregulator that increases AR activity by modulating the AR interdomain interaction.
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Kajiwara, Daisuke, Kazuhisa Minamiguchi, Masanao Seki, Hiroya Mizutani, Hiroki Aoyagi, Shigeo Okajima, Eiji Sasaki, Teruhiro Utsugi, and Yoshikazu Iwasawa. "Effect of a new type androgen receptor antagonist, TAS3681, on ligand-independent AR activation through its AR downregulation activity." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 199. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.199.
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199 Background: Two new therapies, enzalutamide and abiraterone, directed at the androgen receptor (AR) signaling axis, represent important advances in the management of castration-resistant prostate cancer (CRPC). However, eventually almost all of patients acquire resistance to these drugs by a variety of mechanisms. Ligand independent AR activation such as induction of AR splice variants and AR overexpression are major issues of current CRPC progression. In the present study, we report the biological characterization of TAS3681, which is a new AR antagonist with AR downregulation activity, and propose this concept as a potential new approach for the treatment of CRPC. Methods: For assay of AR transactivation, prostate cancer (PCa) cells were transiently transfected with androgen-responsive reporter gene construct. The transfected cells were treated with growth factor and cytokine in steroid-depleted media, and luciferase activity was measured. To evaluate the effect of TAS3681 on AR and c-Myc protein expression, PCa cells were treated with TAS3681 in steroid-depleted media. AR and c-Myc protein levels were determined by western blot. Real-time PCR was used to analyze the mRNA levels of c-Myc and c-Myc target gene. Chromatin immunoprecipitation was performed to determine the enrichment of AR at the element. Results: TAS3681 dose-dependently reduced AR protein levels in PCa cells. In contrast to enzalutamide, TAS3681 suppressed androgen-independent AR transactivation by growth factor and cytokine. In PCa cells which express full-length AR and splice variant AR-v7, TAS3681 suppressed AR-v7 target gene expression through downregulation of AR-v7. Moreover, TAS3681 reduced expression of c-Myc, critical driver of androgen-independent mechanisms of PCa progression, via AR downregulation activity. In addition, real-time PCR assay showed the transcriptional suppression of c-Myc and its target gene by TAS3681. Conclusions: TAS3681 exhibits suppressive effects on ligand-independent AR activation via AR decreasing activity. These finding suggest that TAS3681 could be a candidate of breakthrough therapy for resistance to current AR pathway target drugs.
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Patrão, Marilia T. C. C., Erick J. R. Silva, and Maria Christina W. Avellar. "Androgens and the male reproductive tract: an overview of classical roles and current perspectives." Arquivos Brasileiros de Endocrinologia & Metabologia 53, no. 8 (November 2009): 934–45. http://dx.doi.org/10.1590/s0004-27302009000800006.
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Androgens are steroid hormones that play key roles in the development and maintenance of male phenotype and reproductive function. These hormones also affect the function of several non-reproductive organs, such as bone and skeletal muscle. Endogenous androgens exert most of their effects by genomic mechanisms, which involve hormone binding to the androgen receptor (AR), a ligand-activated transcription factor, resulting in the modulation of gene expression. AR-induced non-genomic mechanisms have also been reported. A large number of steroidal and non-steroidal AR-ligands have been developed for therapeutic use, including the treatment of male hypogonadism (AR agonists) and prostate diseases (AR antagonists), among other pathological conditions. Here, the AR gene and protein structure, mechanism of action and AR gene homologous regulation were reviewed. The AR expression pattern, its in vivo regulation and physiological relevance in the developing and adult testis and epididymis, which are sites of sperm production and maturation, respectively, were also presented.
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Kazmin, Dmitri, Tatiana Prytkova, C. Edgar Cook, Russell Wolfinger, Tzu-Ming Chu, David Beratan, J. D. Norris, Ching-yi Chang, and Donald P. McDonnell. "Linking Ligand-Induced Alterations in Androgen Receptor Structure to Differential Gene Expression: A First Step in the Rational Design of Selective Androgen Receptor Modulators." Molecular Endocrinology 20, no. 6 (June 1, 2006): 1201–17. http://dx.doi.org/10.1210/me.2005-0309.
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Abstract We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful selective AR modulators. To this end, we used combinatorial peptide phage display coupled with molecular dynamic structure analysis to identify the surfaces on AR that are exposed specifically in the presence of selected AR ligands. Subsequently, we used a DNA microarray analysis to demonstrate that differently conformed receptors facilitate distinct patterns of gene expression in LNCaP cells. Interestingly, we observed a complete overlap in the identity of genes expressed after treatment with mechanistically distinct AR ligands. However, it was differences in the kinetics of gene regulation that distinguished these compounds. Follow-up studies, in cell-based assays of AR action, confirmed the importance of these alterations in gene expression. Together, these studies demonstrate an important link between AR structure, gene expression, and biological outcome. This relationship provides a firm underpinning for mechanism-based screens aimed at identifying SARMs with useful clinical profiles.
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Rosenblatt, Adena E., and Kerry L. Burnstein. "Inhibition of Androgen Receptor Transcriptional Activity as a Novel Mechanism of Action of Arsenic." Molecular Endocrinology 23, no. 3 (March 1, 2009): 412–21. http://dx.doi.org/10.1210/me.2008-0235.
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Abstract Environmental sodium arsenite is a toxin that is associated with male infertility due to decreased and abnormal sperm production. Arsenic trioxide (ATO), another inorganic trivalent semimetal, is an effective therapy for acute promyelocytic leukemia, and there is investigation of its possible efficacy in prostate cancer. However, the mechanism of arsenic action in male urogenital tract tissues is not clear. Because the androgen receptor (AR) plays an important role in spermatogenesis and prostate cancer, we explored the possibility that trivalent arsenic regulates AR function. We found that arsenic inhibited AR transcriptional activity in prostate cancer and Sertoli cells using reporter gene assays testing several androgen response element-containing regions and by assessing native target gene expression. Arsenic inhibition of AR activity was not due to down-regulation of AR protein levels, decreased hormone binding to AR, disruption of AR nuclear translocation, or interference with AR-DNA binding in vitro. However, chromatin immunoprecipitation studies revealed that arsenic inhibited AR recruitment to an AR target gene enhancer in vivo. Consistent with a deficiency in AR-chromatin binding, arsenic disrupted AR amino and carboxyl termini interaction. Furthermore, ATO caused a significant decrease in prostate cancer cell proliferation that was more pronounced in cells expressing AR compared with cells depleted of AR. In addition, inhibition of AR activity by ATO and by the AR antagonist, bicalutamide, was additive. Thus, arsenic-induced male infertility may be due to inhibition of AR activity. Further, because AR is an important target in prostate cancer therapy, arsenic may serve as an effective therapeutic option.
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Weil, S. J., K. Vendola, J. Zhou, O. O. Adesanya, J. Wang, J. Okafor, and C. A. Bondy. "Androgen Receptor Gene Expression in the Primate Ovary: Cellular Localization, Regulation, and Functional Correlations." Journal of Clinical Endocrinology & Metabolism 83, no. 7 (July 1, 1998): 2479–85. http://dx.doi.org/10.1210/jcem.83.7.4917.
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Excess androgens are associated with a characteristic polyfollicular ovarian morphology; however, it is not known to what extent this problem is due to direct androgen action on follicular development vs. interference with gonadotropin release at the level of the pituitary or hypothalamus. To elucidate potential androgen effects on the ovary, we investigated the cellular localization of androgen receptor (AR) messenger ribonucleic acid (mRNA) in rhesus monkey using in situ hybridization. To investigate the regulation of ovarian AR gene expression, we compared the relative abundance of AR transcripts in monkeys during follicular and luteal phases of the menstrual cycle and in monkeys treated with testosterone. To assess potential functional consequences of AR expression in the primate ovary, we compared AR mRNA levels with indexes of follicular cell proliferation and apoptosis in serial sections from individual follicles. AR mRNA expression was most abundant in granulosa cells of healthy preantral and antral follicles in the primate ovary. Theca interna and stromal cells also expressed AR mRNA, but to a lesser degree than granulosa cells. No significant cycle stage effects were noted in AR mRNA levels; however, larger numbers of animals would be necessary to definitively establish a cycle stage effect. AR mRNA level was significantly increased in granulosa cells and was decreased in theca interna and stromal cells of testosterone-treated monkeys. Importantly, granulosa cell AR mRNA abundance was positively correlated with expression of the proliferation-specific antigen Ki-67 (r = 0.91; P < 0.001) and negatively correlated with granulosa cell apoptosis (r = −0.64; P < 0.001). In summary, these data show that primate ovary AR gene expression is most abundant in granulosa cells of healthy growing follicles, where its expression is up-regulated by testosterone. The positive correlation between granulosa AR gene expression and cell proliferation and negative correlation with programmed cell death suggests that androgens stimulate early primate follicle development.
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Cremonini, Anna, Luca Saragoni, Luca Morandi, Angelo G. Corradini, Caterina Ravaioli, Enrico Di Oto, Francesco Limarzi, et al. "Chromosome X aneusomy and androgen receptor gene copy number aberrations in apocrine carcinoma of the breast." Virchows Archiv 479, no. 2 (February 3, 2021): 345–54. http://dx.doi.org/10.1007/s00428-021-03028-2.
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AbstractCarcinomas with apocrine differentiation (CAD) of the breast are rare tumours typically presenting high immunohistochemical expression of androgen receptor (AR) which is a target molecule for personalised therapy. To date, no studies have evaluated the genetic changes that are associated with AR immunohistochemical expression in CADs. The present work aims to characterise AR status in CADs. Twenty CAD tumours were studied with immunohistochemistry, in situ fluorescence hybridization and DNA methylation analysis, to evaluate AR expression and its regulator status. All tumours demonstrated high AR immunohistochemical expression, with over 95% of the neoplastic cells showing AR positivity in 19/20 cases. CADs showed AR gene copy loss in a percentage of neoplastic cells ranging from 5 to 84% (mean 48.93%). AR regulator genes, including the MAGE family, UXT and FLNA, presented variable methylation levels, but were mainly hypomethylated and therefore all transcriptionally active. The results of this study indicate that CADs present AR monosomy, paralleled by higher transcriptional activity of the gene with potential to influence response to AR deprivation therapy.
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Deutsch, Dan. "Structure and function of enamel gene products." Anatomical Record 224, no. 2 (June 1989): 189–210. http://dx.doi.org/10.1002/ar.1092240209.
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Zhao, Xueying, Yuanyuan Zhang, Michelle Leander, Lingyun Li, Guoshen Wang, and Nerimiah Emmett. "Altered Expression Profile of Renalα1D-Adrenergic Receptor in Diabetes and Its Modulation by PPAR Agonists." Journal of Diabetes Research 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/725634.
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Alpha1D-adrenergic receptor (α1D-AR) plays important roles in regulating physiological and pathological responses mediated by catecholamines, particularly in the cardiovascular and urinary systems. The present study was designed to investigate the expression profile ofα1D-AR in the diabetic kidneys and its modulation by activation of peroxisome proliferator-activated receptors (PPARs). 12-week-old Zucker lean (ZL) and Zucker diabetic fatty (ZD) rats were treated with fenofibrate or rosiglitazone for 8–10 weeks. Gene microarray, real-time PCR, and confocal immunofluorescence microscopy were performed to assess mRNA and protein expression ofα1D-AR in rat kidney tissue. Using microarray, we found thatα1D-AR gene was dramatically upregulated in 22-week-old ZD rats compared to ZL controls. Quantitative PCR analysis verified a 16-fold increase inα1D-AR mRNA in renal cortex from ZD animals compared to normal controls. Chronic treatment with fenofibrate or rosiglitazone reduced renal corticalα1D-AR gene. Immunofluorescence staining confirmed thatα1D-AR protein was induced in the glomeruli and tubules of diabetic rats. Moreover, dual immunostaining forα1D-AR and kidney injury molecule-1 indicated thatα1D-AR was expressed in dedifferentiated proximal tubules of diabetic Zucker rats. Taken together, our results show thatα1D-AR expression is upregulated in the diabetic kidneys. PPAR activation suppressed renal expression ofα1D-AR in diabetic nephropathy.
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Bainbridge, Alex, Scott Walker, Joseph Smith, Kathryn Patterson, Aparna Dutt, Yi Min Ng, Huw D. Thomas, et al. "IKBKE activity enhances AR levels in advanced prostate cancer via modulation of the Hippo pathway." Nucleic Acids Research 48, no. 10 (April 23, 2020): 5366–82. http://dx.doi.org/10.1093/nar/gkaa271.
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Abstract Resistance to androgen receptor (AR) targeting therapeutics in prostate cancer (PC) is a significant clinical problem. Mechanisms by which this is accomplished include AR amplification and expression of AR splice variants, demonstrating that AR remains a key therapeutic target in advanced disease. For the first time we show that IKBKE drives AR signalling in advanced PC. Significant inhibition of AR regulated gene expression was observed upon siRNA-mediated IKBKE depletion or pharmacological inhibition due to inhibited AR gene expression in multiple cell line models including a LNCaP derivative cell line resistant to the anti-androgen, enzalutamide (LNCaP-EnzR). Phenotypically, this resulted in significant inhibition of proliferation, migration and colony forming ability suggesting that targeting IKBKE could circumvent resistance to AR targeting therapies. Indeed, pharmacological inhibition in the CWR22Rv1 xenograft mouse model reduced tumour size and enhanced survival. Critically, this was validated in patient-derived explants where enzymatic inactivation of IKBKE reduced cell proliferation and AR expression. Mechanistically, we provide evidence that IKBKE regulates AR levels via Hippo pathway inhibition to reduce c-MYC levels at cis-regulatory elements within the AR gene. Thus, IKBKE is a therapeutic target in advanced PC suggesting repurposing of clinically tested IKBKE inhibitors could be beneficial to castrate resistant PC patients.
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Liu, Yan-Nian, Ying Liu, Han-Jung Lee, Yung-Hsiang Hsu, and Ji-Hshiung Chen. "Activated Androgen Receptor Downregulates E-Cadherin Gene Expression and Promotes Tumor Metastasis." Molecular and Cellular Biology 28, no. 23 (September 15, 2008): 7096–108. http://dx.doi.org/10.1128/mcb.00449-08.
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ABSTRACT The loss of E-cadherin gene expression can cause the dysfunction of the cell-cell junction to trigger tumor metastasis. Members of the Snail family of transcription factors are repressors of the expression of the E-cadherin gene. In this study, we showed that the activated androgen receptor (AR) is a novel repressor of E-cadherin gene expression and can promote metastasis. Our results demonstrated that the activated AR could bind to the E-cadherin promoter in vitro and in vivo. The activated AR and HDAC1 had synergistic effects in downregulating E-cadherin gene expression. Treating cells with the AR ligand, dihydrotestosterone (DHT), triggered the reduction of E-cadherin expression and induced changes in cell morphology from an epithelial-like to a mesenchymal-like appearance. When nonmetastatic breast cancer cells expressing cytoplasmic AR were transplanted into mice and the mice were treated with DHT, tumors were detected at metastatic sites, whereas no tumors were detected in transplanted mice without DHT treatment. Furthermore, clinical data from breast cancer patients with invasive ductal carcinomas showed high levels of AR expression in the nuclei and low levels of E-cadherin expression. These results suggest that, similarly to Snail and Twist, the activated AR can downregulate E-cadherin expression to promote the activation of epithelial-mesenchymal transition and tumor metastasis.
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LI, XIAOJING, and HUA H. WANG. "Tetracycline Resistance Associated with Commensal Bacteria from Representative Ready-to-Consume Deli and Restaurant Foods." Journal of Food Protection 73, no. 10 (October 1, 2010): 1841–48. http://dx.doi.org/10.4315/0362-028x-73.10.1841.
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Proper knowledge of antibiotic resistance (AR) dissemination is essential for effective mitigation. This study examined the profiles of tetracycline-resistant (Tetr) commensal bacteria from representative ready-to-consume food samples from salad bars at local grocery stores and restaurants. Out of 900 Tetr isolates examined, 158 (17.6%) carried one or more of tetM, tetL, tetS, and tetK genes by conventional PCR, 28 harbored more than one Tetr determinants. The most prevalent genotype was tetM, which was detected in 70.9% of the AR gene carriers, followed by tetL (31.6%), tetS (13.9%), and tetK (2.5%). Identified AR gene carriers included Enterococcus, Lactococcus, Staphylococcus, Brochothrix, Carnobacterium, Stenotrophomonas, Pseudomonas, and Sphingobacterium, by 16S rRNA gene sequence analysis. AR determinants were successfully transmitted, and led to resistance in Streptococcus mutans via natural gene transformation and Enterococcus faecalis via electroporation, suggesting the functionality and mobility of the AR genes from the food commensal bacteria. In addition, the AR traits in many isolates are quite stable, even in the absence of the selective pressure. The identification of new commensal carriers for representative AR genes revealed the involvement of a broad spectrum of bacteria in the horizontal transmission of AR genes. Meanwhile, the spectrum of the antibiotic-resistant bacteria differed from the spectrum of the total bacteria (by denaturing gradient gel electrophoresis) associated with the food items. Our data revealed a common avenue in AR exposure and will assist in proper risk assessment and the development of comprehensive mitigation strategies to effectively combat AR.
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Chen, Honglin, Stephen J. Libertini, Michael George, Satya Dandekar, Clifford G. Tepper, Bushra Al-Bataina, Hsing-Jien Kung, Paramita M. Ghosh, and Maria Mudryj. "Genome-wide analysis of androgen receptor binding and gene regulation in two CWR22-derived prostate cancer cell lines." Endocrine-Related Cancer 17, no. 4 (December 2010): 857–73. http://dx.doi.org/10.1677/erc-10-0081.
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Prostate carcinoma (CaP) is a heterogeneous multifocal disease where gene expression and regulation are altered not only with disease progression but also between metastatic lesions. The androgen receptor (AR) regulates the growth of metastatic CaPs; however, sensitivity to androgen ablation is short lived, yielding to emergence of castrate-resistant CaP (CRCaP). CRCaP prostate cancers continue to express the AR, a pivotal prostate regulator, but it is not known whether the AR targets similar or different genes in different castrate-resistant cells. In this study, we investigated AR binding and AR-dependent transcription in two related castrate-resistant cell lines derived from androgen-dependent CWR22-relapsed tumors: CWR22Rv1 (Rv1) and CWR-R1 (R1). Expression microarray analysis revealed that R1 and Rv1 cells had significantly different gene expression profiles individually and in response to androgen. In contrast, AR chromatin immunoprecipitation (ChIP) combined with promoter DNA microarrays (ChIP-on-chip) studies showed that they have a similar AR-binding profile. Coupling of the microarray study with ChIP-on-chip analysis identified direct AR targets. The most prominent function of transcripts that were direct AR targets was transcriptional regulation, although only one transcriptional regulator, CCAAT/enhancer binding protein δ, was commonly regulated in both lines. Our results indicate that the AR regulates the expression of different transcripts in the two lines, and demonstrate the versatility of the AR-regulated gene expression program in prostate tumors.
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Wang, Bi-Dar, Qi Yang, Kristin Ceniccola, Fernando Bianco, Ramez Andrawis, Thomas Jarrett, Harold Frazier, Steven R. Patierno, and Norman H. Lee. "Androgen Receptor-Target Genes in African American Prostate Cancer Disparities." Prostate Cancer 2013 (2013): 1–15. http://dx.doi.org/10.1155/2013/763569.
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The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter analysis revealed that 382 out of 1,188 genes containedcis-acting AR-binding sequences. Chromatin immunoprecipitation confirmedSTAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A,1andPIK3CBgenes as novel AR targets in PCa disparities. Moreover, functional screens revealed that androgen-stimulated AR binding and upregulation ofRHOA, ITGB5,andPIK3CBgenes were associated with increased invasive activity of AA PCa cells, as siRNA-mediated knockdown of each gene caused a loss of androgen-stimulated invasion. In summation, our findings demonstrate that transcriptional changes have preferentially occurred in multiple signaling pathways converging (“transcriptional convergence”) on AR signaling, thereby contributing to AR-target gene activation and PCa aggressiveness in AAs.
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Gurioli, Giorgia, Vincenza Conteduca, Umberto Basso, Giuseppe Fornarini, Alessandra Mosca, Maurizio Nicodemo, Giuseppe Luigi Banna, et al. "Gene expression in circulating tumor cells (CTC) and plasma androgen receptor (AR) gene copy number (CN) for castration-resistant prostate cancer (CRPC) patients (pts) treated with cabazitaxel." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 154. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.154.
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154 Background: Cabazitaxel demonstrated overall survival (OS) benefit for the treatment of CRPC progressing after docetaxel. CTC profiling could help to establish novel predictive biomarkers. In this prospective study (NCT03381326), we evaluated the prognostic role of CTC biomarkers expression and the association with plasma AR CN in pts treated with cabazitaxel. Methods: We enrolled pts receiving cabazitaxel from January 2015 to December 2018. Plasma DNA was isolated and digital PCR was performed to assess AR CN status. CTC enrichment was evaluated with AdnaTest EMT-2/StemCell kit. Expression analyses using real time PCR were performed for 17 genes and CTC positivity (CTC+) was defined as the expression of at least 1 of the following 7 relevant markers: AR-V7, AKT, AR, EPCAM, PSMA, PI3KCA, PSCA. Results: We enrolled 100 pts, 80 fully evaluable for this analysis. Median age was 72 years (range 49-82). All pts received prior docetaxel and 85% prior abiraterone and/or enzalutamide. Median OS and progression-free survival (PFS) were 16.4 months (mo) (95% CI 11.1-27.0) and 6.7 mo (95% CI 5.2-8.3), respectively. Fifty-eight (72.5%) showed CTC+ at baseline, whose 15 (26%) had >3 markers expressed in CTC. Significantly worse OS was observed in pts with >3 markers expressed in CTC compared to those with ≤3 markers and CTC negative pts [4.7 mo vs 15.2 vs 31.7 mo respectively, hazard ratio (HR) 6.05 (95% CI 2.07-17.73), p=0.004]. No significant difference was observed for PFS and PSA response. AR-V7 was expressed in 11 (19%) CTC+ pts, whose 10 (91%) had >3 markers expressed in CTC (p=0.0274), and 8 (73%) had plasma AR CN gain (p=0.048). A shorter OS was observed in AR-V7+ vs AR-V7- pts [10.6 vs 18.1 mo, HR 2.48 (95% CI 1.00-6.18), p=0.051]. Significantly worse OS and PFS were found in AR CN gain pts compared to AR normal [11.1 mo vs 27.0 mo, HR 2.28 (95% CI 1.19-4.38), p=0.013 and 5.9 mo vs 8.5 mo, HR 1.81 (95% CI 1.05-3.13), p=0.032], respectively. Conclusions: Liquid biopsy profiling may improve prognostication of CRPC patients treated with cabazitaxel. Further larger studies are warranted. Funding: Partially funded by Sanofi Genzyme. Clinical trial information: NCT03381326.
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Choudhry, M. A., and I. J. McEwan. "In vitro regulation of reporter gene transcription by the androgen receptor AF1 domain." Biochemical Society Transactions 32, no. 6 (October 26, 2004): 1103–6. http://dx.doi.org/10.1042/bst0321103.
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The androgen receptor (AR) is a ligand-activated transcription factor that regulates gene expression in response to the steroids testosterone and dihydrotestosterone. AR-dependent gene expression is likely to play an important role in a number of receptor-associated disorders, such as prostate cancer, spinal bulbar muscular atrophy, male type baldness and hirsutism. The AR contains two transactivation domains, termed AF1 (activation function 1) located in the N-terminus and AF2 (activation function 2) in the C-terminal ligand-binding domain. AF2 exhibits weak transcriptional activity, whereas AF1 is a strong regulator of transcription. Transcriptional regulation by AF1 is thought to be modulated by a number of proteins that interact with this region, and by post-translational modifications. Our focus is on the N-terminal-interacting proteins and their regulation of transcription via interaction with the receptor. To better understand the mechanism of AR-AF1 action, we have reconstituted AR activity in HeLa nuclear extracts using a unique dual reporter gene assay. Multiple LexA-binding sites in the promoter allow transcription to be driven by a recombinant AR-AF1–Lex fusion protein. The findings from initial experiments suggest an increase in transcription initiation and elongation rates by AR-AF1–Lex. The role of protein–protein interactions involving co-activators and basal transcription factors and AR-AF1 activity are discussed.
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Nan, B., T. Snabboon, E. Unni, Yuan X-J, YE Whang, and M. Marcelli. "The PTEN tumor suppressor is a negative modulator of androgen receptor transcriptional activity." Journal of Molecular Endocrinology 31, no. 1 (August 1, 2003): 169–83. http://dx.doi.org/10.1677/jme.0.0310169.
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To investigate whether the tumor suppressor gene PTEN affects the activity of the androgen receptor (AR), we monitored the expression of the apoptotic gene HA-Bax (inserted in an adenovirus where it is driven by the AR-responsive promoter ARR(2)PB) in the presence or absence of dihydrotestosterone, in PTEN (+) or (-) prostate cancer cell lines, infected with an adenovirus containing wild-type PTEN (Av-CMV-PTEN) or a control LacZ-expressing construct. Our results showed that AR transcriptional activity was antagonized by PTEN expression. This antagonism was not cell line dependent, as it was observed in both LNCaP and LAPC-4 cells, or promoter dependent, as it was observed for a reporter gene (HA-Bax) driven by an exogenous androgen-responsive promoter (the ARR(2)PB promoter), and for a native gene (prostate-specific antigen; PSA) driven by an endogenous AR-responsive promoter. Additional experiments performed with viruses containing constitutively active (Adeno-myrAkt) or dominant negative (Adeno-dnAkt) forms of Akt demonstrated that Akt, a protein kinase whose activation is known to be inhibited by PTEN, mediated the observed antagonism between PTEN and AR transcriptional activity. Recently, two putative Akt phosphorylation sites have been identified in the AR sequence. Site-directed mutagenesis was utilized to convert these two serine into alanine residues. The resulting construct, named CMV-AR S213A&S791A was transfected in AR (-) and PTEN (-) PC-3 cells in the presence or absence of Av-CMV-PTEN and of two reporter plasmids (GRE(2)E1b-Luc and PSA P/E-luc) containing the luciferase gene driven by well-characterized androgen responsive promoters. These experiments demonstrated that, similarly to the wild-type molecule, AR S213A&S791A was transcriptionally inhibited by PTEN, suggesting that Akt does not have an effect on AR transcription by direct phosphorylation, but probably by affecting the availability of a downstream molecule whose main mechanism of action is that of modulating AR transcription. The data presented here suggest that loss of PTEN function may facilitate activation of AR signaling and progression to androgen independence in prostate cancer.
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Yamane, Kunikazu, Yohei Doi, Keiko Yokoyama, Tetsuya Yagi, Hiroshi Kurokawa, Naohiro Shibata, Keigo Shibayama, Haru Kato, and Yoshichika Arakawa. "Genetic Environments of the rmtA Gene in Pseudomonas aeruginosa Clinical Isolates." Antimicrobial Agents and Chemotherapy 48, no. 6 (June 2004): 2069–74. http://dx.doi.org/10.1128/aac.48.6.2069-2074.2004.
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ABSTRACT Nine Pseudomonas aeruginosa strains showing very high levels of resistance to various aminoglycosides have been isolated from clinical specimens in seven separate Japanese hospitals in five prefectures since 1997. These strains harbor the newly identified 16S rRNA methylase gene (rmtA). When an rmtA gene probe was hybridized with genomic DNAs of the nine strains digested with EcoRI, two distinct patterns were observed. The 11.1- and 15.8-kb regions containing the rmtA genes of strains AR-2 and AR-11, respectively, were sequenced and compared. In strain AR-2, a transposase gene-like sequence (sequence 1) and a probable tRNA ribosyltransferase gene (orfA) were located upstream of rmtA, and a Na+/H+ antiporter gene-like sequence (sequence 2) was identified downstream of rmtA. This 6.2-kbp insert (the rmtA locus) was flanked by 262-bp κγ elements. Part of the orfQ gene adjacent to an inverted repeat was found outside of the rmtA locus. In strain AR-11, the rmtA gene and sequence 2 were found, but the 5′ end of the orfA gene was truncated and replaced with IS6100. An orfQ-orfI region was present on each side of the rmtA gene in strain AR-11. The G+C content of the rmtA gene was about 55%, and since the newly identified rmtA gene may well be mediated by some mobile genetic elements such as Tn5041, further dissemination of the rmtA gene could become an actual clinical problem in the near future.
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Konno, Akitsugu, Miho Inoue-Murayama, and Toshikazu Hasegawa. "Androgen receptor gene polymorphisms are associated with aggression in Japanese Akita Inu." Biology Letters 7, no. 5 (March 30, 2011): 658–60. http://dx.doi.org/10.1098/rsbl.2011.0087.
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We tested for an association between variable number of tandem repeats in the canine androgen receptor ( AR ) gene and personality differences in Japanese Akita Inu dogs. The polymorphic trinucleotide (CAG) repeat region coding for glutamine in exon 1 of the AR gene was genotyped using genomic DNA obtained from 171 dogs. Three alleles ( 23 , 24 and 26 repeats) were detected, and the allele frequency differed with the coat colour. We assessed the personality profiles of 100 fawn-coloured dogs (54 males and 46 females) based on a questionnaire answered by each dog's owner. The questionnaire consisted of five sub-scales (sociability, playfulness, neuroticism, aggressiveness, distractibility), and the psychometric properties were acceptable based upon internal consistency of the subscales. We found that male dogs with a short allele conferring increased AR function had higher aggressiveness scores than male dogs with longer alleles. By contrast, no evidence was found for a relationship between AR gene variants and personality in females. To our knowledge, our findings provide the first evidence of polymorphism in the AR gene being associated with canine aggression.
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Kato, Harumi, Kazuhito Yamamoto, Kennosuke Karube, Miyuki Katayama, Shinobu Tsuzuki, Yasushi Yatabe, Jun Takizawa, et al. "Gene Expression Profiling of Age-Related Epstein-Barr Virus (EBV)-Associated B-Cell Lymphoproliferative Disorder Uncovers Alterations in Immune and Inflammatory Genes: Possible Implications for Pathogenesis,." Blood 118, no. 21 (November 18, 2011): 3448. http://dx.doi.org/10.1182/blood.v118.21.3448.3448.
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Abstract Abstract 3448 Age-related EBV-associated B-cell lymphoproliferative disorder (AR-EBLPD) is classified as a subtype of diffuse large cell lymphoma (DLBCL) according to the WHO classification. However, molecular genetic characterization of AR-EBLPD remains largely unknown. We studied expression profiles of 5 AR-EBLPD and 8 EB-negative DLBCL samples using the Agilent 44K human oligonucleotide microarray. Total RNA was extracted from fresh-frozen tumor samples. Each microarray slide was converted into datasets using the Agilent Micro Array Scanner and Feature extractions. Data was standardized with Z-scores. Differences in mRNA expression levels between two sample groups were calculated using a two-sided t-test. A total of 1973 probes showed a p-value less than 0.05 with less than a 25% false discovery rate (FDR). These probes included 1688 genes. The number of probes showing high expression in AR-EBLPD and EB-negative DLBCL was 804 (693 genes) and 1169 (995 genes), respectively. First, we selected the top 300 differentially expressed genes. Genes highly expressed in AR-EBLPD included IL6, TNFAIP3, HOPX, and SLAMF1. IL6 is known as a gene encoding a cytokine which functions in inflammation and the maturation of B lymphocytes, and TNFAIP3 is known as a negative regulatory gene of the NF-kB pathway. HOPX and SLAMF1 are reported as genes related to lymphocyte function or the immune system (Schwartzberg et al. Nature immunology 2009, Hawiger et al. Nature immunology 2011). For better characterization, we next performed Gene Ontology Analysis using the WEB-based GEne SeT AnaLysis Toolkit and found that categories of external stimulus and inflammatory responses were enriched in AR-EBLPD. The Kyoto Encyclopedia of Genes and Genomes (KEGG)-signaling analyses showed that pathways of the NOD-like receptor (p-value =1.30e-06), JAK-STAT (p-value =9.01e-06), and Toll-like receptor (p-value =0.0002) were characteristic of AR-EBLPD. These results implied that inflammation would be prominent in AR-EBLPD cases. For validation, we next performed Gene Set Enrichment Analysis (GSEA) using all the database of KEGG pathways (186 gene sets). Dominant gene sets in AR-EBLPD included the cytokine-cytokine receptor interaction [Normalized Enrichment Score (NES) =2.66, p-value<0.001], NOD-like receptor pathway (NES =2.26, p-value<0.001), TOLL-like receptor pathway (NES =2.14, p-value<0.001), and JAK-STAT pathway (NES =1.79, p-value<0.001). Since all the pathways were related to the NF-kB pathway, inflammatory responses were suggested to activate the NF-kB pathway or vice versa. For confirmation, we finally performed GSEA using gene sets of the NF-kB pathway, which were obtained from a gene set reported by an NIH group (Puente et al. Nature 2011) and 30 gene sets in the GSEA database, and found that the gene sets of the NF-kB pathway were enriched in AR-EBLPD (Figure 1). Our results suggested that the inflammatory and immune-related genes were enriched in AR-EBLPD and that activation of the genes may be associated with NF-kB activation. Aberrant immune and inflammatory responses could define the clinical presentations of AR-EBLPD cases. (Figure 1) Gene Set Enrichment Analysis of 5 AR-EBLPD and 8 EB-negative DLBCL samples. The NF-kB signature reported from an NIH group (Puente et al. Nature 2011) was enriched in AR-EBLPD [Normalized Enrichment Score (NES) =2.20, p-value<0.001]. Disclosures: No relevant conflicts of interest to declare.
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Sucharov, Carmen C., Peter D. Mariner, Karin R. Nunley, Carlin Long, Leslie Leinwand, and Michael R. Bristow. "A β1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 3 (September 2006): H1299—H1308. http://dx.doi.org/10.1152/ajpheart.00017.2006.
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β-Adrenergic signaling plays an important role in the natural history of dilated cardiomyopathies. Chronic activation of β-adrenergic receptors (β1-AR and β2-AR) during periods of cardiac stress ultimately harms the failing heart by mechanisms that include alterations in gene expression. Here, we show that stimulation of β-ARs with isoproterenol in neonate rat ventricular myocytes causes a “fetal” response in the relative activities of the human cardiac fetal and/or adult gene promoters that includes repression of the human and rat α-myosin heavy chain (α-MyHC) promoters with simultaneous activation of the human atrial natriuretic peptide (ANP) and rat β-MyHC promoters. We also show that the promoter changes correlate with changes in endogenous gene expression as measured by mRNA expression. Furthermore, we show that these changes are specifically mediated by the β1-AR, but not the β2-AR, and are independent of α1-AR stimulation. We also demonstrate that the fetal gene response is independent of cAMP and protein kinase A, whereas inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK) pathway blocks isoproterenol-mediated fetal gene program induction. Finally, we show that induction of the fetal program is dependent on activation of the L-type Ca2+ channel. We conclude that in neonatal rat cardiac myocytes, agonist-occupied β1-AR mobilizes Ca2+ stores to activate fetal gene induction through cAMP independent pathways that involve CaMK.
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Holterhus, Paul-Martin, Hennie T. Brüggenwirth, Olaf Hiort, Annette Kleinkauf-Houcken, Klaus Kruse, Gernot H. G. Sinnecker, and Albert O. Brinkmann. "Mosaicism due to a Somatic Mutation of the Androgen Receptor Gene Determines Phenotype in Androgen Insensitivity Syndrome1." Journal of Clinical Endocrinology & Metabolism 82, no. 11 (November 1, 1997): 3584–89. http://dx.doi.org/10.1210/jcem.82.11.4375.
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Premature stop codons of the human androgen receptor (AR) gene are usually associated with a complete androgen insensitivity syndrome. We, however, identified an adult patient with a 46,XY karyotype carrying a premature stop codon in exon 1 of the AR gene presenting with signs of partial virilization: pubic hair Tanner stage 4 and clitoral enlargement. No other family members were affected. A point mutation at codon position 172 of the AR gene was detected that replaced the original TTA (Leu) with a premature stop codon TGA (opal). Careful examination of the sequencing gel, however, also identified a wild-type allele, indicating a mosaicism. In addition, elimination of the unique AflII recognition site induced by the mutation was incomplete, thus confirming the coexistence of mutant and wild-type AR alleles in the patient. Normal R1881 binding and a normal 110/112-kDa AR doublet in Western immunoblots consolidated the molecular genetic data by demonstrating the expression of the wild-type AR in the patient’s genital skin fibroblasts. Transfection analysis revealed that only relatively high plasmid concentrations carrying the mutated AR complementary DNA lead to expression of a shortened AR due to downstream reinitiation at methionine 189. Thus, reinitiation does not play a role in the presentation of the phenotype; rather, the partial virilization is caused by the expression of the wild-type AR due to a somatic mosaic. We conclude that somatic mosaicism of the AR gene can represent a substantial factor for the individual phenotype by shifting it to a higher degree of virilization than expected from the genotype of the mutant allele alone.
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Zeng, Ximin, and Jun Lin. "Factors influencing horizontal gene transfer in the intestine." Animal Health Research Reviews 18, no. 2 (December 2017): 153–59. http://dx.doi.org/10.1017/s1466252317000159.
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AbstractAntibiotic resistance (AR) is ancient. Use of antibiotics is a selective driving force that enriches AR genes and promotes the emergence of resistant pathogens. It also has been widely accepted that horizontal gene transfer (HGT) occurs everywhere and plays a critical role in the transmission of AR genes among bacteria. However, our understanding of HGT processes primarily build on extensivein vitrostudies; to date, there is still a significant knowledge gap regardingin situHGT events as well as the factors that influence HGT in different ecological niches. This review is focused on the HGT process in the intestinal tract, a ‘melting pot’ for gene exchange. Several factors that potentially influencein vivoHGT efficiency in the intestine are identified and summarized, which include SOS-inducing agents, stress hormones, microbiota and microbiota-derived factors. We highlight recent discoveries demonstrating that certain antibiotics, which are widely used in animal industry, can enhance HGT in the intestine by serving as DNA-damaging, SOS-inducing agents. Despite recent progress, research onin vivoHGT events is still in its infancy. A better understanding of the factors influencing HGT in the intestine is highly warranted for developing effective strategies to mitigate AR in animal production as well as in future agricultural ecosystems.
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Russell, Patricia K., Salvatore Mangiafico, Barbara C. Fam, Michele V. Clarke, Evelyn S. Marin, Sofianos Andrikopoulos, Kristine M. Wiren, Jeffrey D. Zajac, and Rachel A. Davey. "The androgen receptor in bone marrow progenitor cells negatively regulates fat mass." Journal of Endocrinology 237, no. 1 (April 2018): 15–27. http://dx.doi.org/10.1530/joe-17-0656.
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It is well established that testosterone negatively regulates fat mass in humans and mice; however, the mechanism by which testosterone exerts these effects is poorly understood. We and others have shown that deletion of the androgen receptor (AR) in male mice results in a phenotype that mimics the three key clinical aspects of hypogonadism in human males; increased fat mass and decreased bone and muscle mass. We now show that replacement of the Ar gene specifically in mesenchymal progenitor cells (PCs) residing in the bone marrow of Global-ARKO mice, in the absence of the AR in all other tissues (PC-AR Gene Replacements), completely attenuates their increased fat accumulation. Inguinal subcutaneous white adipose tissue and intra-abdominal retroperitoneal visceral adipose tissue depots in PC-AR Gene Replacement mice were 50–80% lower than wild-type (WT) and 75–90% lower than Global-ARKO controls at 12 weeks of age. The marked decrease in subcutaneous and visceral fat mass in PC-AR Gene Replacements was associated with an increase in the number of small adipocytes and a healthier metabolic profile compared to WT controls, characterised by normal serum leptin and elevated serum adiponectin levels. Euglycaemic/hyperinsulinaemic clamp studies reveal that the PC-AR Gene Replacement mice have improved whole-body insulin sensitivity with higher glucose infusion rates compared to WT mice and increased glucose uptake into subcutaneous and intra-abdominal fat. In conclusion, these data provide the first evidence for an action of androgens via the AR in mesenchymal bone marrow PCs to negatively regulate fat mass and improve metabolic function.
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Landero-Huerta, Daniel A., Rosa M. Vigueras-Villaseñor, Lucía Taja-Chayeb, Fabiola García-Andrade, Elena Aréchaga-Ocampo, Emiy Yokoyama-Rebollar, José Díaz-Chávez, Luis A. Herrera, and Margarita D. Chávez-Saldaña. "Analysis of the CAG tract length in the Androgen Receptor gene in Mexican patients with nonsyndromic cryptorchidism." Journal of Pediatric Endocrinology and Metabolism 34, no. 7 (April 12, 2021): 843–49. http://dx.doi.org/10.1515/jpem-2020-0378.
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Abstract Objectives Cryptorchidism is the most common genitourinary birth defect in live newborn males and is considered as an important risk factor for testicular germ cell tumors and infertility. The Androgen Receptor gene is important in this pathology due to its participation, mainly, in the inguinoscrotal phase of testicular descent. We determine the length of the CAG tract in the Androgen Receptor (AR) gene in Mexican patients with nonsyndromic cryptorchidism. Methods One hundred and 15 males were included; of these, 62 had nonsyndromic cryptorchidism and 53 were healthy volunteers. DNA was extracted from a peripheral blood samples, subsequently, the CAG tract in exon 1 of AR gene was amplified by PCR and sequenced. Results Mexican patients with nonsyndromic cryptorchidism presented 25.03 ± 2.58 repeats of CAG tract in the AR gene compared to 22.72 ± 3.17 repeats of CAG tract in Mexican healthy individuals (p≤0.0001; t value of 4.3). Furthermore, the deletion of codon 57 that corresponds to the deletion of a leucine residue at position 57 (Del L57) in the AR gene was found for the first time in a nonsyndromic cryptorchidism patient. This molecular alteration has been related previously to testicular germ cell tumor (TGCT). Conclusions The CAG tract in the AR gene is longer in patients with nonsyndromic cryptorchidism than in healthy individuals, supporting the association between this polymorphism of the AR gene and nonsyndromic cryptorchidism in the Mexican population.
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Patel, Ojas P., Ralph C. Giorno, Donald A. Dibbern, Karen Y. Andrews, Sonia Durairaj, and Stephen C. Dreskin. "Gene Expression Profiles in Chronic Idiopathic (Spontaneous) Urticaria." Allergy & Rhinology 6, no. 2 (January 2015): ar.2015.6.0124. http://dx.doi.org/10.2500/ar.2015.6.0124.
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Background The pathophysiology of chronic idiopathic (spontaneous) urticaria (CIU) is poorly understood. Objective We hypothesized that a study of gene expression in active lesions from patients with CIU would uncover unexpected associations. Methods We enrolled eight patients with CIU and six healthy controls, and obtained 4 mm punch biopsy specimens of active lesions and unaffected skin of patients with CIU and of skin from normal controls. Routine histologic evaluation was performed, RNA was isolated, and gene expression data were assessed. Due to technical reasons, the final evaluation included six samples of lesional skin, six samples of nonlesional skin, and five samples of normal skin. Results As expected, lesional skin had more inflammatory cells per high-powered field (mean ± SE, 96 ± 6) than did samples from nonlesional skin of the subjects with CIU (17 ± 2) (p < 0.01). Lesions of CIU showed significant upregulation of 506 genes and reduced expression of 51 genes. Those most upregulated were predominantly involved in cell adhesion (e.g., selectin E [SELE]), cell activation (e.g., CD69), and chemotaxis (e.g., CCL2). Twelve independent canonical pathways with p ≤ 0.001 were identified (including intracellular kinase pathways (RAs-related nuclear protein [RAN] and Janus activated kinase/interferon), cytokine signaling pathways (IL-9, IL10, and IFN), a strong inflammatory response (interferon, IL-9, IL-10, inducible nitric oxide synthase and glucocorticoid pathways) and increased cell proliferation (RAN signaling, cell cycle control, and tRNA charging). Conclusions This preliminary study describes a method to study gene activation in urticarial lesions and demonstrated a strong inflammatory response with a large variety of activated genes that are distinct from those reported with other dermatologic conditions.
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Yamagishi, Toshiyuki, Katsumi Ando, Hiroaki Nakamura, and Yuji Nakajima. "Expression of the Tgfβ2 Gene During Chick Embryogenesis." Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology 295, no. 2 (December 21, 2011): 257–67. http://dx.doi.org/10.1002/ar.22400.
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Peng, Yang, Wei-jie Guan, Zhen-chao Zhu, Kai Sen Tan, Zhuo Chen, Hai-yu Hong, Xiao-xue Zi, et al. "Microarray Assay Reveals Ciliary Abnormalities of the Allergic Nasal Mucosa." American Journal of Rhinology & Allergy 34, no. 1 (August 26, 2019): 50–58. http://dx.doi.org/10.1177/1945892419871795.
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Background Gene expression patterns (particularly, cilia-associated genes) of nasal mucosa, the first-line defense system, in allergic rhinitis (AR) are not well understood. Objective We sought to screen for AR-associated genes in inferior turbinate (IT) from patients with AR, and to validate the expression of common cilia-related genes and ciliary shedding. Methods Prime View™ Human Gene Expression Array, which consisted of more than 530 000 probes covering more than 36 000 transcripts and variants, was employed to compare individual gene expression of ITs from control subjects (n = 11) and patients with AR (n = 19). Gene ontology (GO) analysis was performed with Cytoscape software. Eight of the common cilia-related genes were validated with quantitative polymerase chain reaction. We applied a semiquantitative scoring system for immunofluorescence assay to demonstrate ciliary shedding in 5 areas per paraffin section, with individual sections being scored between 0 (normal ciliary distribution) and 1 (ciliary shedding). Results Compared with control subjects, 160 (38 upregulated and 122 downregulated) genes were differentially expressed for at least 2 folds (all P < .05) in AR. Seven GO categories were significantly enriched, 4 of which were related to cilium assembly and motility. Quantitative polymerase chain reaction validated the predicted direction of change for common cilia-related gene expression. The ciliary distribution score was significantly higher (more prominent ciliary shedding) in AR than in controls ( P < .05). Conclusion The significant aberrant cilia-related gene expression, revealed by microarray assays, might be the critical driver of AR where ciliary shedding is prominent.
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Westberg, Lars, Fariba Baghaei, Roland Rosmond, Monika Hellstrand, Mikael Landén, Maria Jansson, Göran Holm, Per Björntorp, and Elias Eriksson. "Polymorphisms of the Androgen Receptor Gene and the Estrogen Receptor β Gene Are Associated with Androgen Levels in Women1." Journal of Clinical Endocrinology & Metabolism 86, no. 6 (June 1, 2001): 2562–68. http://dx.doi.org/10.1210/jcem.86.6.7614.
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To elucidate the possible role of genetic variation in androgen receptor (AR), estrogen receptor α (ERα), and ERβ on serum androgen levels in premenopausal women, the CAG repeat polymorphism of the AR gene, the TA repeat polymorphism of the ERα gene, and the CA repeat polymorphism of the ERβ gene were studied in a population-based cohort of 270 women. Total testosterone, free testosterone, dehydroepiandrosterone sulfate, androstenedione, 17-hydroxyprogesterone, 3α-androstanediol glucuronide, 17β-estradiol, LH, FSH, and sex steroid hormone-binding globulin (SHBG) were measured in serum samples obtained in the follicular phase of the menstrual cycle. Women with relatively few CAG repeats in the AR gene, resulting in higher transcriptional activity of the receptor, displayed higher levels of serum androgens, but lower levels of LH, than women with longer CAG repeat sequences. The CA repeat of the ERβ gene also was associated with androgen and SHBG levels; women with relatively short repeat regions hence displayed higher hormone levels and lower SHBG levels than those with many CA repeats. In contrast, the TA repeat of the ERα gene was not associated with the levels of any of the hormones measured. Our results suggest that the serum levels of androgens in premenopausal women may be influenced by variants of the AR gene and the ERβ gene, respectively.
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Madjunkova, S., A. Eftimov, V. Georgiev, D. Petrovski, A. Dimovski, and D. Plaseska-Karanfilska. "Cag Repeat Number in the Androgen Receptor Gene and Prostate Cancer." Balkan Journal of Medical Genetics 15, no. 1 (January 1, 2012): 31–36. http://dx.doi.org/10.2478/v10034-012-0005-z.
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Cag Repeat Number in the Androgen Receptor Gene and Prostate CancerProstate cancer (PC) is the second leading cause of cancer deaths in men. The effects of androgens on prostatic tissue are mediated by the androgen receptor (AR) gene. The 5' end of exon 1 of the AR gene includes a polymorphic CAG triplet repeat that numbers between 10 to 36 in the normal population. The length of the CAG repeats is inversely related to the transactivation function of the AR gene. There is controversy over association between short CAG repeat numbers in the AR gene and PC. This retrospective case-control study evaluates the possible effect of short CAG repeats on the AR gene in prostate cancer risk in Macedonian males. A total of 392 male subjects, 134 PC patients, 106 patients with benign prostatic hyperplasia (BPH) and 152 males from the general Macedonian population were enrolled in this study. The CAG repeat length was determined by fluorescent polymerase chain reaction (PCR) amplification of exon1 of the AR gene followed by capillary electrophoresis (CE) on a genetic analyzer. The mean repeat length in PC patients was 21.5 ±2.65, in controls 22.28 ±2.86 (p = 0.009) and in BPH patients 22.1 ±2.52 (p = 0.038). Short CAG repeats (<19) were found in 21.64% of PC patients vs. 9.43% in BPH patients (p = 0.0154). We also found an association of low Gleason score (<7) with short CAG repeat (<19) in PC patients (p = 0.0306), and no association between the age at diagnosis of PC and BPH and CAG repeat length. These results suggest that reduced CAG repeat length may be associated with increased prostate cancer risk in Macedonian men.
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Giwercman, Yvonne Lundberg, Agneta Nordenskjöld, E. Martin Ritzén, Karl Olof Nilsson, Sten-A. Ivarsson, Ulla Grandell, and Anna Wedell. "An Androgen Receptor Gene Mutation (E653K) in a Family with Congenital Adrenal Hyperplasia due to Steroid 21-Hydroxylase Deficiency as well as in Partial Androgen Insensitivity." Journal of Clinical Endocrinology & Metabolism 87, no. 6 (June 1, 2002): 2623–28. http://dx.doi.org/10.1210/jcem.87.6.8518.
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An androgen receptor (AR) variant (E653K) was found in two unrelated Swedish families. One family had two girls affected with congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency. The girls, who showed mild virilization in relation to their CYP21 genotype, had inherited the AR gene mutation from their father, who showed no symptoms of androgen insensitivity. The other family had a boy with partial androgen insensitivity and ambiguous genitalia, and he had inherited the AR gene mutation from his mother. The mutant receptor showed a transactivating capacity in the same range as the normal receptor at high concentrations of ligand (1 and 10 nm dihydrotestosterone), but absent or reduced transactivation at low levels (0.01 and 0.1 nm). The receptor variant was not found among 250 additional unselected Swedish men. Sequencing of the AR gene in five unrelated CAH girls with the I172N mutation in CYP21 and minimal virilization did not reveal any additional deviations from the normal reference sequence. In addition, there was no difference in lengths of the polymorphic CAG repeat in the AR gene between CAH girls with the I172N mutation who showed minimal and severe virilization, and we found no evidence of skewed X-inactivation. We conclude that AR gene mutations or polymorphisms are not a common factor influencing the degree of hyperandrogenic symptoms displayed by CAH girls, and that the AR E653K mutation is compatible with normal genital development, although it can cause genital malformations in susceptible individuals.
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Hong, Cheol Yi, Ji Ho Suh, Kabsun Kim, Eun-Yeung Gong, Sung Ho Jeon, Myunggon Ko, Rho Hyun Seong, Hyuk Bang Kwon, and Keesook Lee. "Modulation of Androgen Receptor Transactivation by the SWI3-Related Gene Product (SRG3) in Multiple Ways." Molecular and Cellular Biology 25, no. 12 (June 15, 2005): 4841–52. http://dx.doi.org/10.1128/mcb.25.12.4841-4852.2005.
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ABSTRACT The SWI3-related gene product (SRG3), a component of the mouse SWI/SNF complex, has been suggested to have an alternative function. Here, we demonstrate that in the prostate transactivation of the androgen receptor (AR) is modulated by SRG3 in multiple ways. The expression of SRG3, which is developmentally regulated in the prostate, is induced by androgen through AR. SRG3 in turn enhances the transactivation of AR, providing a positive feedback regulatory loop. The SRG3 coactivation of AR transactivation is achieved through the recruitment of coactivator SRC-1, the protein level of which is upregulated by SRG3, providing another pathway of positive regulation. Interestingly, SRG3 coactivation of AR transactivation is fully functional in BRG1/BRM-deficient C33A cells and the AR/SRG3/SRC-1 complex formed in vivo contains neither BRG1 nor BRM protein, suggesting the possibility of an SRG3 function independent of the SWI/SNF complex. Importantly, the AR/SRG3/SRC-1 complex occupies androgen response elements on the endogenous SRG3 and PSA promoter in an androgen-dependent manner in mouse prostate and LNCaP cells, respectively, inducing gene expression. These results suggest that the multiple positive regulatory mechanisms of AR transactivation by SRG3 may be important for the rapid proliferation of prostate cells during prostate development and regeneration.
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Batista, Rafael Loch, Katsumi Yamaguchi, Andresa di Santi Rodrigues, Mirian Yumie Nishi, John L. Goodier, Luciani Renata Carvalho, Sorahia Domenice, Elaine M. F. Costa, Haig H. Kazazian, and Berenice Bilharinho Mendonca. "Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome." Journal of Clinical Endocrinology & Metabolism 104, no. 12 (August 8, 2019): 6385–90. http://dx.doi.org/10.1210/jc.2019-00144.
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Abstract Context Androgen insensitivity syndrome (AIS) is the most common cause of disorders of sex development in 46,XY individuals. It is an X-linked condition usually caused by pathogenic allelic variants in the androgen receptor (AR) gene. The phenotype depends on the AR variant, ranging from severe undervirilization (complete AIS) to several degrees of external genitalia undervirilization. Although 90% of those with complete AIS will have AR mutations, this will only be true for 40% of those with partial AIS (PAIS). Objective To identify the genetic etiology of AIS in a large multigenerational family with the PAIS phenotype. Participants Nine affected individuals with clinical and laboratory findings consistent with PAIS and a normal exonic AR sequencing Settings Endocrine clinic and genetic institute from two academic referral centers Design Analysis of whole exons of the AR gene, including splicing regions, was performed, followed by sequencing of the 5′untranslated region (UTR) of the AR gene. Detailed phenotyping was performed at the initial diagnosis and long-term follow-up, and circulating levels of steroid gonadal hormones were measured in all affected individuals. AR expression was measured using RT-PCR and cultured fibroblasts. Results All 46,XY family members with PAIS had inherited, in hemizygosity, a complex defect (∼1100 bp) in the 5′UTR region of the AR surrounded by a duplicated 18-bp sequence (target site duplication). This sequence is 99.7% similar to an active, long, interspersed element present on the X chromosome (AC002980; Xq22.2), which was inserted in the 5′UTR of the AR gene, severely reducing AR expression and leading to PAIS. Conclusion The molecular diagnosis of PAIS remains challenging. The genomic effect of retrotransposon mobilization should be considered a possible molecular cause of AIS and other AR diseases.
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Nicholson, Wayne L. "The Bacillus subtilis ydjL (bdhA) Gene Encodes Acetoin Reductase/2,3-Butanediol Dehydrogenase." Applied and Environmental Microbiology 74, no. 22 (September 26, 2008): 6832–38. http://dx.doi.org/10.1128/aem.00881-08.
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ABSTRACT Bacillus subtilis is capable of producing 2,3-butanediol from acetoin by fermentation, but to date, the gene encoding the enzyme responsible, acetoin reductase/2,3-butanediol dehydrogenase (AR/BDH), has remained unknown. A search of the B. subtilis genome database with the amino acid sequences of functional AR/BDHs from Saccharomyces cerevisiae and Bacillus cereus resulted in the identification of a highly similar protein encoded by the B. subtilis ydjL gene. A knockout strain carrying a ydjL::cat insertion mutation was constructed, which (i) abolished 2,3-butanediol production in early stationary phase, (ii) produced no detectable AR or BDH activity in vitro, and (iii) accumulated the precursor acetoin in early stationary phase. The ydjL::cat mutation also affected the kinetics of lactate but not acetate production during stationary-phase cultivation with glucose under oxygen limitation. A very small amount of 2,3-butanediol was detected in very-late-stationary-phase (96-hour) cultures of the ydjL::cat mutant, suggesting the existence of a second gene encoding a minor AR activity. From the data, it is proposed that the major AR/BDH-encoding gene ydjL be renamed bdhA.