scholarly journals Regulation of the androgen receptor by post-translational modifications

2012 ◽  
Vol 215 (2) ◽  
pp. 221-237 ◽  
Author(s):  
Kelly Coffey ◽  
Craig N Robson
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Steroid Receptor ◽  
Signalling Pathway ◽  
Regulatory Mechanisms ◽  
Post Translational Modifications ◽  
Kennedy’S Disease ◽  
Kennedy's Disease ◽  
Functional Consequences ◽  
Disease Understanding

The androgen receptor (AR) is a key molecule in prostate cancer and Kennedy's disease. Understanding the regulatory mechanisms of this steroid receptor is important in the development of potential therapies for these diseases. One layer of AR regulation is provided by post-translational modifications including phosphorylation, acetylation, sumoylation, ubiquitination and methylation. While these modifications have mostly been studied as individual events, it is becoming clear that these modifications can functionally interact with each other in a signalling pathway. In this review, the effects of all modifications are described with a focus on interplay between them and the functional consequences for the AR.

Structural dynamics of the human androgen receptor: implications for prostate cancer and neurodegenerative disease

2006 ◽  
Vol 34 (6) ◽  
pp. 1098-1102 ◽  
Author(s):  
J. Duff ◽  
P. Davies ◽  
K. Watt ◽  
I.J. McEwan
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Structural Dynamics ◽  
Muscular Atrophy ◽  
Binding Domain ◽  
Genetic Changes ◽  
Kennedy’S Disease ◽  
Kennedy's Disease ◽  
Exon 1 ◽  
Spinal Bulbar Muscular Atrophy

The AR (androgen receptor) is a ligand-activated transcription factor that mediates the action of the steroids testosterone and dihydrotestosterone. Alterations in the AR gene result in a number of clinical disorders, including: androgen-insensitivity, which leads to disruption of male development; prostate cancer; and a neuromuscular degenerative condition termed spinal bulbar muscular atrophy or Kennedy's disease. The AR gene is X-linked and the protein is coded for by eight exons, giving rise to a C-terminal LBD (ligand-binding domain; exons 4–8), linked by a hinge region (exon 4) to a Zn-finger DBD (DNA-binding domain; exons 2 and 3) and a large structurally distinct NTD (N-terminal domain; exon 1). Identification and characterization of mutations found in prostate cancer and Kennedy's disease patients have revealed the importance of structural dynamics in the mechanisms of action of receptors. Recent results from our laboratory studying genetic changes in the LBD and the structurally flexible NTD will be discussed.

scholarly journals Androgen Receptor Signalling in Prostate Cancer: The Functional Consequences of Acetylation

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Derek N. Lavery ◽  
Charlotte L. Bevan
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Histone Deacetylases ◽  
Transcriptional Response ◽  
Fine Tuning ◽  
Receptor Signalling ◽  
Prostate Carcinogenesis ◽  
Functional Consequences

The androgen receptor (AR) is a ligand activated transcription factor and member of the steroid hormone receptor (SHR) subfamily of nuclear receptors. In the early stages of prostate carcinogenesis, tumour growth is dependent on androgens, and AR directly mediates these effects by modulating gene expression. During transcriptional regulation, the AR recruits numerous cofactors with acetylation-modifying enzymatic activity, the best studied include p300/CBP and the p160/SRC family of coactivators. It is known that recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) is key in fine-tuning responses to androgens and is thus likely to play a role in prostate cancer progression. Further, these proteins can also modify the AR itself. The functional consequences of AR acetylation, the role of modifying enzymes in relation to AR transcriptional response, and prostate cancer will be discussed.

Kennedy's disease: A clinicopathologic correlation with mutations in the androgen receptor gene

Neurology ◽  
1993 ◽  
Vol 43 (4) ◽  
pp. 791-791 ◽  
Author(s):  
A. A. Amato ◽  
T. W. Prior ◽  
R. J. Barohn ◽  
P. Snyder ◽  
A. Papp ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Receptor Gene ◽  
Androgen Receptor Gene ◽  
Kennedy’S Disease ◽  
Clinicopathologic Correlation ◽  
Kennedy's Disease

scholarly journals X-linked spinal and bulbar muscular atrophy (Kennedy’s disease): the first case described in the Brazilian Amazon

2018 ◽  
Vol 16 (2) ◽  
Author(s):  
Camila Nascimento Alves ◽  
Tiago Kiyoshi Kitabayashi Braga ◽  
Danusa Neves Somensi ◽  
Bruno Sérgio Vilhena do Nascimento ◽  
José Antônio Santos de Lima ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Muscular Atrophy ◽  
Receptor Gene ◽  
Brazilian Amazon ◽  
Androgen Receptor Gene ◽  
Thoracic Spinal Cord ◽  
Kennedy’S Disease ◽  
Kennedy's Disease ◽  
First Case ◽  
Patient Reported

ABSTRACT The X-linked spinal and bulbar muscular atrophy (Kennedy’s disease) is a rare X-linked, recessive, lower motor neuron disease, characterized by weakness, atrophy, and fasciculations of the appendicular and bulbar muscle. The disease is caused by an expansion of the CAG repetition in the androgen receptor gene. Patients with Kennedy’s disease have more than 39 CAG repetitions. We report a case of 57-year-old man, resident of Monte Dourado (PA, Brazil) who complained of brachiocrural paresis evolving for 3 years along with fasciculations and tremors of extremities. In addition, he also developed dysarthria, dysphagia, and sexual dysfunction. The patient clinical picture included gait impairment, global hyporeflexia, proximal muscle atrophy of upper limbs, deviation of the uvula to right during phonation and tongue atrophy with fasciculations. The patient reported that about 30 years ago he had undergone gynecomastia surgery. His electroneuromyography suggested spinal muscular atrophy, and nuclear magnetic resonance imaging showed tapering of the cervical and thoracic spinal cord. Patient’s creatine kinase level was elevated. In view of the findings, an exam was requested to investigate Kennedy’s disease. The exam identified 46 CAG repetitions in the androgen receptor gene, which confirmed the diagnostic suspicion. This was the first case of Kennedy’s disease diagnosed and described in the Brazilian Amazon. To our knowledge only other four papers were published on this disease in Brazilian patients. A brief review is also provided on etiopathogenic, clinical and diagnostic aspects.

Abnormal androgen receptor binding affinity in subjects with Kennedy's disease (spinal and bulbar muscular atrophy).

1995 ◽  
Vol 80 (2) ◽  
pp. 508-516 ◽  
Author(s):  
H E MacLean ◽  
W T Choi ◽  
G Rekaris ◽  
G L Warne ◽  
J D Zajac
Keyword(s):  
Androgen Receptor ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Muscular Atrophy ◽  
Receptor Binding Affinity ◽  
Kennedy’S Disease ◽  
Kennedy's Disease

scholarly journals Androgen receptor corepressors and prostate cancer

2006 ◽  
Vol 13 (4) ◽  
pp. 979-994 ◽  
Author(s):  
Craig J Burd ◽  
Lisa M Morey ◽  
Karen E Knudsen
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Steroid Hormones ◽  
Regulatory Mechanisms ◽  
Cancer Growth ◽  
Tumor Type ◽  
Concerted Effort ◽  
Androgen Action ◽  
Prostate Cancers

The androgen receptor (AR) mediates the effects of male steroid hormones (androgens) and contributes to a wide variety of physiological and pathophysiological conditions. As such, the regulatory mechanisms governing AR activity are of high significance. Concerted effort has been placed on delineating the mechanisms that control AR activity in prostate cancer, as AR is required for survival and proliferation in this tumor type. Moreover, AR is the central therapeutic target for metastatic prostate cancers, and recurrent tumors evade therapy by restoring AR activity. It is increasingly apparent that AR cofactors which modulate receptor activity can contribute to prostate cancer growth or progression, and this has been particularly well established for AR coactivators. The present review is focused on the role of AR corepressors in governing androgen action, with a specific emphasis on their activities in prostate cancer.

scholarly journals Androgen receptor phosphorylation: biological context and functional consequences

2014 ◽  
Vol 21 (4) ◽  
pp. T131-T145 ◽  
Author(s):  
Yulia Koryakina ◽  
Huy Q Ta ◽  
Daniel Gioeli
Keyword(s):  
Transcription Factor ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Androgen Insensitivity Syndrome ◽  
Clinical Samples ◽  
Post Translational Modifications ◽  
Wide Range ◽  
Functional Consequences ◽  
Biological Context

The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is also regulated by post-translational modifications generated by signal transduction pathways. Thus, the AR functions not only as a transcription factor but also as a node that integrates multiple extracellular signals. The AR plays an important role in many diseases, including complete androgen insensitivity syndrome, spinal bulbar muscular atrophy, prostate and breast cancer, etc. In the case of prostate cancer, dependence on AR signaling has been exploited for therapeutic intervention for decades. However, the effectiveness of these therapies is limited in advanced disease due to restoration of AR signaling. Greater understanding of the molecular mechanisms involved in AR action will enable the development of improved therapeutics to treat the wide range of AR-dependent diseases. The AR is subject to regulation by a number of kinases through post-translational modifications on serine, threonine, and tyrosine residues. In this paper, we review the AR phosphorylation sites, the kinases responsible for these phosphorylations, as well as the biological context and the functional consequences of these phosphorylations. Finally, what is known about the state of AR phosphorylation in clinical samples is discussed.

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