Androgens inhibit androgen receptor promoter activation in motor neurons

Vismara, Guglielmo; Simonini, F.; Onesto, Elisa; Bignamini, Marta; Miceli, V.; Martini, L.; Poletti, Angelo

doi:10.1016/j.nbd.2008.11.007

Cited by 25 publications

(23 citation statements)

References 48 publications

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“…4d). Our data are consistent with earlier observations that deletion of the section from +570 to +1,025 bp (containing the 5′ UTR ARE) in luciferase reporters driven by the hAR promoter and 5′ UTR does not completely abrogate downregulation by androgens [36]. A growing body of work has elucidated some of the signalling pathways by which this can occur through the regulatory elements present in the luciferase reporter (Fig.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, the clinically relevant antiandrogens, bicalutamide and enzalutamide were unable to mediate receptor-dependent repression. These observations were made independently of Vismara et al [36] who suggested a putative nonclassical ARE in the 5′ UTR. In contrast to that study, we have demonstrated the binding of AR and functional relevance of this element in different prostate cell lines.…”

Section: Discussionmentioning

confidence: 73%

“…Only a previously described suggested nonconsensus ARE (AGAACCctcTGTTTT) at position 611 bp in the 5′ UTR of exon 1 [36] was revealed (Fig. 1b).…”

Section: Resultsmentioning

confidence: 82%

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Negative Regulation of the Androgen Receptor Gene Through a Primate-Specific Androgen Response Element Present in the 5′ UTR

et al. 2014

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The androgen receptor (AR) is a widely expressed ligand-activated transcription factor which mediates androgen signalling by binding to androgen response elements (AREs) in normal tissue and prostate cancer (PCa). Within tumours, the amount of AR plays a crucial role in determining cell growth, resistance to therapy and progression to fatal castrate recurrent PCa in which prostate cells appear to become independent of androgenic steroids. Despite the pivotal role of the AR in male development and fertility and all stages of PCa development, the mechanisms governing AR expression remain poorly understood. In this work, we describe an active nonconsensus androgen response element (ARE) in the 5′ UTR of the human AR gene. The ARE represses transcription upon binding of activated AR, and this downregulation is relieved by disruption of the regulatory element through mutation. Also, multiple species comparison of the genomic region reveals that this ARE is specific to primates, leading to the conclusion that care must be exercised when elucidating the operation of the human AR in PCa based upon rodent promoter studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s12672-014-0185-y) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 73%

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Negative Regulation of the Androgen Receptor Gene Through a Primate-Specific Androgen Response Element Present in the 5′ UTR

et al. 2014

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“…The AR/Jarid1b binding on DNA of target gene seems to be allowed by the presence of Androgen Responsive Element (ARE) and by the presence of binding sites for the histone demethylases enzyme, Jarid1b (PLU1) and AhR (XRE), (Casati et al, 2013). As a matter of fact, in our previous studies, where the AR promoter DNA sequence was analyzed, we observed the presence of binding sites for Jarid1b (PLU1), some AREs, and XREs (Casati et al, 2013) [which at the same time suggests for a potential direct effect of the Jarid1b in modulating also the AR negative auto feedback (Vismara et al, 2009)]. In order to study the AR/Jarid1b interaction, we performed a series of gene reporter assays, where HEK293 cells were cotransfected with plasmids encoding for the luciferase gene, under the control of AR promoters with different lengths (long, intermediate and short), and the Jarid1b gene (Casati et al, 2013).…”

Section: A Hypothesis: How the Eds Could Affect The Epigenome? A Linkmentioning

confidence: 80%

Endocrine disrupters: the new players able to affect the epigenome

Casati

Sendra

Sibilia

et al. 2015

Front. Cell Dev. Biol.

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Epigenetics represents the way by which the environment is able to program the genome; there are three main levels of epigenetic control on genome: DNA methylation, post-translational histone modification and microRNA expression. The term Epigenetics has been widened by NIH to include “both heritable changes in gene activity and expression but also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable.” These changes might be produced mostly by the early life environment and might affect health influencing the susceptibility to develop diseases, from cancer to mental disorder, during the entire life span. The most studied environmental influences acting on epigenome are diet, infections, wasting, child care, smoking and environmental pollutants, in particular endocrine disrupters (EDs). These are environmental xenobiotics able to interfere with the normal development of the male and female reproductive systems of wildlife, of experimental animals and possibly of humans, disrupting the normal reproductive functions. Data from literature indicate that EDs can act at different levels of epigenetic control, in some cases transgenerationally, in particular when the exposure to these compounds occurs during the prenatal and earliest period of life. Some of the best characterized EDs will be considered in this review. Among the EDs, vinclozolin (VZ), and methoxychlor (MXC) promote epigenetic transgenerational effects. Polychlorinated biphenils (PCBs), the most widespread environmental EDs, affect histone post-translational modifications in a dimorphic way, possibly as the result of an alteration of gene expression of the enzymes involved in histone modification, as the demethylase Jarid1b, an enzyme also involved in regulating the interaction of androgens with their receptor.

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“…Some of the therapeutic strategies that have been tested in SBMA include gene silencing, protein quality control and/or increased protein degradation, androgen deprivation, and modulation of AR activity and functions. Evidence from various studies that include both in vitro and in vivo models support a role for testosterone binding and nuclear translocation of the AR as the trigger for SBMA [21][22][23][24][25][26][27]. However, trails using antiandrogen therapy, commonly used in the treatment of advanced prostate cancer, yielded disappointing findings, despite highly promising animal studies.…”

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confidence: 99%

Spinal bulbar muscular atrophy, an inherited neurodegenerative disease: Potential mechanisms and therapeutic targets

Kumar¹

2017

J Syst Integr Neurosci

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Instability of CAG triplet repeat encoding poly-glutamine (polyQ) stretch in the androgen receptor (AR) gene has been implicated as a putative mechanism in spinal bulbar muscular atrophy (SBMA) or Kennedy's disease. Although the underlying mechanisms are not completely understood, suggested pathological pathways of SBMA involve the formation of AR nuclear and cytoplasmic aggregates. Here we discuss the role of polyQ chain length extension in the pathophysiology of SBMA and the potential therapeutic targets.

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Androgens inhibit androgen receptor promoter activation in motor neurons

Cited by 25 publications

References 48 publications

Negative Regulation of the Androgen Receptor Gene Through a Primate-Specific Androgen Response Element Present in the 5′ UTR

Negative Regulation of the Androgen Receptor Gene Through a Primate-Specific Androgen Response Element Present in the 5′ UTR

Endocrine disrupters: the new players able to affect the epigenome

Spinal bulbar muscular atrophy, an inherited neurodegenerative disease: Potential mechanisms and therapeutic targets

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