Transcriptional activation by the androgen receptor in X-linked spinal and bulbar muscular atrophy

The androgen receptor (AR) is a ligand-regulated transcription factor that stimulates cell growth and differentiation in androgen-responsive tissues. The AR N terminus contains two activation functions (AF-1a and AF-1b) that are necessary for maximal transcriptional enhancement by the receptor; however, the mechanisms and components regulating AR transcriptional activation are not fully understood. We sought to identify novel factors that interact with the AR N terminus from an androgen-stimulated human prostate cancer cell library using a yeast two-hybrid approach designed to identify proteins that interact with transcriptional activation domains. A 157-amino acid protein termed ART-27 was cloned and shown to interact predominantly with the AR153–336, containing AF-1a and a part of AF-1b, localize to the nucleus and increase the transcriptional activity of AR when overexpressed in cultured mammalian cells. ART-27 also enhanced the transcriptional activation by AR153–336 fused to the LexA DNA-binding domain but not other AR N-terminal subdomains, suggesting that ART-27 exerts its effect via an interaction with a defined region of the AR N terminus. ART-27 interacts with AR in nuclear extracts from LNCaP cells in a ligand-independent manner. Interestingly, velocity gradient sedimentation of HeLa nuclear extracts suggests that native ART-27 is part of a multiprotein complex. ART-27 is expressed in a variety of human tissues, including sites of androgen action such as prostate and skeletal muscle, and is conserved throughout evolution. Thus, ART-27 is a novel cofactor that interacts with the AR N terminus and plays a role in facilitating receptor-induced transcriptional activation.

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Native Functions of the Androgen Receptor Are Essential to Pathogenesis in a Drosophila Model of Spinobulbar Muscular Atrophy

Neuron ◽

10.1016/j.neuron.2010.08.034 ◽

2010 ◽

Vol 67 (6) ◽

pp. 936-952 ◽

Cited By ~ 116

Author(s):

Natalia B. Nedelsky ◽

Maria Pennuto ◽

Rebecca B. Smith ◽

Isabella Palazzolo ◽

Jennifer Moore ◽

...

Keyword(s):

Androgen Receptor ◽

Muscular Atrophy ◽

Spinobulbar Muscular Atrophy ◽

Drosophila Model

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Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy

Neurology ◽

10.1212/wnl.42.12.2300 ◽

1992 ◽

Vol 42 (12) ◽

pp. 2300-2300 ◽

Cited By ~ 129

Author(s):

S. Igarashi ◽

Y. Tanno ◽

O. Onodera ◽

M. Yamazaki ◽

S. Sato ◽

...

Keyword(s):

Androgen Receptor ◽

Strong Correlation ◽

Muscular Atrophy ◽

Cag Repeats ◽

Clinical Onset

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ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor

Nature Medicine ◽

10.1038/nm1547 ◽

2007 ◽

Vol 13 (3) ◽

pp. 348-353 ◽

Cited By ~ 107

Author(s):

Zhiming Yang ◽

Yu-Jia Chang ◽

I-Chen Yu ◽

Shuyuan Yeh ◽

Cheng-Chia Wu ◽

...

Keyword(s):

Androgen Receptor ◽

Muscular Atrophy

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Consequences of poly-glutamine repeat length for the conformation and folding of the androgen receptor amino-terminal domain

Journal of Molecular Endocrinology ◽

10.1677/jme-08-0042 ◽

2008 ◽

Vol 41 (5) ◽

pp. 301-314 ◽

Cited By ~ 37

Author(s):

Philippa Davies ◽

Kate Watt ◽

Sharon M Kelly ◽

Caroline Clark ◽

Nicholas C Price ◽

...

Keyword(s):

Androgen Receptor ◽

Structural Changes ◽

Muscular Atrophy ◽

Cell Signalling ◽

Limited Proteolysis ◽

Amino Terminal ◽

Terminal Domain ◽

Helix Structure ◽

Α Helix ◽

Amino Terminal Domain

Poly-amino acid repeats, especially long stretches of glutamine (Q), are common features of transcription factors and cell-signalling proteins and are prone to expansion, resulting in neurodegenerative diseases. The amino-terminal domain of the androgen receptor (AR-NTD) has a poly-Q repeat between 9 and 36 residues, which when it expands above 40 residues results in spinal bulbar muscular atrophy. We have used spectroscopy and biochemical analysis to investigate the structural consequences of an expanded repeat (Q45) or removal of the repeat (ΔQ) on the folding of the AR-NTD. Circular dichroism spectroscopy revealed that in aqueous solution, the AR-NTD has a relatively limited amount of stable secondary structure. Expansion of the poly-Q repeat resulted in a modest increase in α-helix structure, while deletion of the repeat resulted in a small loss of α-helix structure. These effects were more pronounced in the presence of the structure-promoting solvent trifluoroethanol or the natural osmolyte trimethylamine N-oxide. Fluorescence spectroscopy showed that the microenvironments of four tryptophan residues were also altered after the deletion of the Q stretch. Other structural changes were observed for the AR-NTDQ45 polypeptide after limited proteolysis; in addition, this polypeptide not only showed enhanced binding of the hydrophobic probe 8-anilinonaphthalene-1-sulphonic acid but was more sensitive to urea-induced unfolding. Taken together, these findings support the view that the presence and length of the poly-Q repeat modulate the folding and structure of the AR-NTD.

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Structural and functional alterations in the androgen receptor in spinal bulbar muscular atrophy

Biochemical Society Transactions ◽

10.1042/bst0290222 ◽

2001 ◽

Vol 29 (2) ◽

pp. 222-227 ◽

Cited By ~ 14

Author(s):

I. J. McEwan

Keyword(s):

Androgen Receptor ◽

Spinocerebellar Ataxia ◽

Muscular Atrophy ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 3 ◽

Diverse Range ◽

Disease States ◽

Associated Proteins ◽

Spinal Bulbar Muscular Atrophy ◽

Clinical Conditions

The androgen receptor is a member of the nuclear receptor superfamily, and regulates gene expression in response to the steroid hormones testosterone and dihydrotestosterone. Mutations in the receptor have been correlated with a diverse range of clinical conditions, including androgen insensitivity, prostate cancer and spinal bulbar muscular atrophy, a neuromuscular degenerative condition. The latter is caused by expansion of a polyglutamine repeat within the N-terminal domain of the receptor. Thus the androgen receptor is one of a growing number of neurodegenerative disease-associated proteins, including huntingtin (Huntington's disease), ataxin-1 (spinocerebellar ataxia, type 1) and ataxin-3 (spinocerebellar ataxia, type 3), which show expansion of CAG triplet repeats. Although widely studied, the functions of huntingtin, ataxin-1 and ataxin-3 remain unknown. The androgen receptor, which has a well-recognized function in gene regulation, provides a unique opportunity to investigate the functional significance of poly(amino acid) repeats in normal and disease states.

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