Transcriptional Repression of the  -Subunit Gene by Androgen Receptor Occurs Independently of DNA Binding but Requires the DNA-Binding and Ligand-Binding Domains of the Receptor

Heckert, L. L.

doi:10.1210/me.11.10.1497

Cited by 24 publications

(26 citation statements)

References 38 publications

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“…Retinoic acid up-regulates the preproTRH gene via an unliganded RAR-RXR mediated mechanism that does not require direct interaction with discrete DNA elements (10). Similarly, transcriptional repression of the ␣ subunit of the pituitary glycoprotein hormones LH and FSH by the AR also occurs independent of direct DNA binding (48). The mechanism of repression requires the DNA binding and ligand binding domains of the receptor, which interact with non-AR elements in the promoter including a cAMP regulatory element.…”

Section: Discussionmentioning

confidence: 99%

Liganded and Unliganded Steroid Receptor Modulation of Beta 1 Adrenergic Receptor Gene Transcription

et al. 2001

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The classical model of gene regulation by hormones involves a hormone-bound receptor interacting with a DNA response element to increase or decrease gene transcription. Steroid hormone regulation more commonly involves atypical cis-elements, co-receptors, accessory proteins, and unique modes of interaction on different genes. The thyroid hormone and retinoic acid receptors belong to the super family of steroid nuclear receptors and may modify gene expression even in the absence of ligand binding. In these studies, we characterized thyroid receptor-and retinoic acid receptor-mediated regulation of ␤1 adrenergic receptor (␤1AR) gene expression. Using cloned fragments of the ovine ␤1AR in a luciferase reporter vector, we examined the effects of thyroid receptor and retinoic acid receptor, alone and in combination with T3 or retinoic acid on ␤1AR expression. We examined expression in SK-N-SH neuroblastoma cells, CV-1 fibroblasts, and, in neonatal rat, primary cardiomyocytes. We demonstrated that even in the absence of ligand binding, thyroid receptor and retinoic acid receptor can significantly increase ␤1AR transcription activity. This effect is important in the developmental transition in ␤1AR expression during fetal and postnatal life. The classical model of gene regulation by hormones involves a hormone-bound receptor interacting with a DNA response element to increase or decrease gene transcription (1, 2). It is now appreciated that this model of hormonal regulation of gene expression is simplistic and may be the exception rather than the rule. For instance, classical models cannot explain the hormonal regulation of genes that lack canonical consensus DNA elements. These models also do not account for changes in hormonal regulation of gene expression at different developmental stages, differential regulation in different tissues, and other complexities of hormonal regulation. Steroid hormone regulation more commonly involves atypical cis-elements, co-receptors, accessory proteins, and unique modes of interaction on different genes (3).The TR and RAR belong to the super family of steroid nuclear receptors (1-4). TR and RAR bind to DNA as heterodimers with RXR (4). There is also a family of coregulators that positively and negatively regulate transcriptional activation from a variety of cis-elements in specific genes. Recently, it has been recognized that modulation of gene expression by steroid nuclear receptors may be independent of ligand binding to the steroid receptor. TR can bind to DNA in the absence of its ligand (thyroid hormone) and can regulate transcription both positively and negatively from a variety of promoters (5-7). Transactivation by TR in the absence of hormone can require cell-specific factors but may occur even with promoters that do not contain clearly defined TRE (8, 9). Similar observations have been reported for RAR (10). A precise physiologic context for nonligand-dependent regulation of transcription by these receptors has not been shown.We are interested in the hormonal regulation of ...

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Section: Discussionmentioning

confidence: 99%

Liganded and Unliganded Steroid Receptor Modulation of Beta 1 Adrenergic Receptor Gene Transcription

et al. 2001

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“…More rarely, AR represses the expression of target genes, with or without DNA interaction (Eacker et al, 2007;Heckert et al, 1997;Palvimo et al, 1996). Furthermore, several AR coregulators, including coactivators or corepressors, have been identified.…”

Section: Microscopy Research and Techniquementioning

confidence: 99%

Ontogeny of the androgen receptor expression in the fetal and postnatal testis: Its relevance on Sertoli cell maturation and the onset of adult spermatogenesis

Rey

Musse

Venara

et al. 2009

Microscopy Res & Technique

143

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From fetal life to adulthood, the testis evolves through maturational phases showing specific morphologic and functional features in its different compartments. The seminiferous cords contain Sertoli and germ cells, surrounded by peritubular cells, and the interstitial tissue contains Leydig cells and connective tissue. Sertoli cells secrete anti-Müllerian hormone (AMH), whereas Leydig cells secrete androgens. In the fetal and early postnatal testis, Leydig cells actively secrete androgens. Sertoli cells are morphologically and functionally immature--e.g., they secrete high levels of AMH--and germ cells proliferate by mitosis but do not enter meiosis. During infancy and childhood, Leydig cells regress and testosterone secretion declines dramatically. Sertoli cells remain immature and spermatogenesis is arrested at the premeiotic stage. At puberty, Leydig cells differentiate again, and testosterone concentration increases and provokes Sertoli cell maturation--e.g., down-regulation of AMH expression--and germ cells undergo meiosis, the hallmark of adult spermatogenesis driving to sperm production. An intriguing feature of testicular development is that, although testosterone production is as active in the fetal and early postnatal periods as in puberty, Sertoli cells and spermatogenesis remain immature until pubertal onset. Here, we review the ontogeny of the androgen receptor expression in the testis and its impact on Sertoli cell maturation and the onset of pubertal spermatogenesis. We show that the absence of androgen receptor expression in Sertoli cells underlies a physiological stage of androgen insensitivity within the male gonad in the fetal and early postnatal periods.

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“…Repression of gene expression by the AR, however, has thus far been found to be independent of binding of the AR to AREs and shown to involve interactions between the AR and other transcriptional regulators. The AR has been found to repress transcription via interactions with nuclear factor-B, activator protein-1 (AP-1), octamer binding transcription factor (Oct)-1 and avian erythroblastosis virus E2 oncogene homolog 1 (Ets-1) as well as cause repression of transcription by competition for coactivators (22)(23)(24)(25)(26). The goal of the current studies was to characterize the molecular mechanisms by which testosterone represses MAFbx expression.…”

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confidence: 99%

Expression of the Muscle Atrophy Factor Muscle Atrophy F-Box Is Suppressed by Testosterone

et al. 2008

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The ubiquitin ligase muscle atrophy F-box (MAFbx; also called atrogin-1) is thought to play important roles in muscle loss. Conversely, testosterone reduces atrophy from glucocorticoids or denervation associated with repression of MAFbx. To characterize mechanisms of such repression, the effects of testosterone on MAFbx expression in C2C12 cells were tested. Testosterone reduced MAFbx mRNA levels as well as expression of a reporter gene under the control of 3.1 kb of the human MAFbx promoter. Repression required the androgen receptor (AR) as well as sequences within the first 208 bases upstream of the first codon of the MAFbx gene. This sequence is downstream of known forkhead transcription factor binding sites and testosterone did not alter Forkhead box O 3A phosphorylation. The AR associated with sequences conferring repression in a manner that was stimulated by testosterone and was independent of DNA binding. In gel shift studies, octamer binding transcription factor (Oct)-1 bound two predicted Oct-1 sites within these sequences. Deletion of Oct-1 sites from reporter genes prevented repression by testosterone. Gene knockdown of Oct-1 blocked repression of MAFbx reporter gene activity by testosterone and binding of AR to sequences conferring repression. In conclusion, testosterone represses MAFbx expression via interactions of the AR with Oct-1 that are associated with sequences within the 5' untranslated region of the MAFbx promotor located just upstream of the first codon. This action of testosterone may contribute to beneficial actions of testosterone on muscle.

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Transcriptional Repression of the -Subunit Gene by Androgen Receptor Occurs Independently of DNA Binding but Requires the DNA-Binding and Ligand-Binding Domains of the Receptor

Cited by 24 publications

References 38 publications

Liganded and Unliganded Steroid Receptor Modulation of Beta 1 Adrenergic Receptor Gene Transcription

Liganded and Unliganded Steroid Receptor Modulation of Beta 1 Adrenergic Receptor Gene Transcription

Ontogeny of the androgen receptor expression in the fetal and postnatal testis: Its relevance on Sertoli cell maturation and the onset of adult spermatogenesis

Expression of the Muscle Atrophy Factor Muscle Atrophy F-Box Is Suppressed by Testosterone

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