Implications of a polyglutamine tract in the function of the human androgen receptor

Callewaert, Leen; Christiaens, Valerie; Haelens, Annemie; Verrijdt, Guy; Verhoeven, Guido; Claessens, Frank

doi:10.1016/s0006-291x(03)00902-1

Cited by 68 publications

(54 citation statements)

References 26 publications

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“…Indeed, we found that the strength of the ligand-induced NTD/LBD interaction is inversely proportional to the length of the poly(Q) region within the AR-NTD. These findings are in agreement with a recent study showing that deletion of the entire AR poly(Q) tract positively affects the NTD/LBD interaction (50). However, our findings contrast an earlier study showing that deletion of the entire AR poly(Q) tract resulted in only a slight increase in ligand binding (8).…”

Section: Discussionsupporting

confidence: 91%

“…Several studies have demonstrated an inverse correlation between the length of the poly(Q) region and AR transcriptional activity (45)(46)(47)(48). Interestingly, truncation or complete deletion of the poly(Q) region can enhance AR-mediated transactivation in the presence of overexpressed p160 proteins (49,50), consistent with the idea that a shortened poly(Q) region can promote coactivator recruitment. However, the detailed molecular mechanisms responsible for the hyperactive transcriptional activity in AR proteins containing shortened poly(Q) regions remain poorly defined.…”

mentioning

confidence: 65%

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Mechanistic Relationship between Androgen Receptor Polyglutamine Tract Truncation and Androgen-dependent Transcriptional Hyperactivity in Prostate Cancer Cells

Wang¹,

Udayakumar²,

Vasaitis

et al. 2004

Journal of Biological Chemistry

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Androgen receptor (AR) signaling pathways mediate critical events in normal and neoplastic prostate growth. Shortening of the polymorphic N-terminal polyglutamine (poly(Q)) tract of the AR gene leads to transcriptional hyperactivity and has been correlated with an increased risk of prostate cancer. The underlying mechanisms for these effects are poorly understood. We show here that androgen-dependent cellular proliferation and transcription in prostate cancer cells is inversely correlated to the length of the AR poly(Q) region. We further show that AR proteins containing a shortened poly(Q) region functionally respond to lower concentrations of androgens than wild type AR. Whereas DNA binding activity is relatively unaffected by AR poly(Q) variation, we found that ligand binding affinity and the ligand-induced NH 2 -to COOH-terminal intramolecular interaction is enhanced when the poly(Q) region is shortened. Importantly, we show that AR proteins containing a shortened poly(Q) region associate in vivo with higher levels of specific p160 coactivators and components of the SWI/SNF chromatin remodeling complex as compared with the wild type AR. Collectively, our findings suggest that the AR transcriptional hyperactivity associated with shortened poly(Q) length stems from altered ligand-induced conformational changes that enhance coactivator recruitment.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 65%

Mechanistic Relationship between Androgen Receptor Polyglutamine Tract Truncation and Androgen-dependent Transcriptional Hyperactivity in Prostate Cancer Cells

Wang¹,

Udayakumar²,

Vasaitis

et al. 2004

Journal of Biological Chemistry

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“…The stabilization of structure or at least a reduction in local structural plasticity may also result from the removal of the poly-Q repeat, with concomitant impact on protein-protein interactions. Expansion of the poly-Q repeat in the AR is proposed to lead to a receptor protein that is compromised for transcriptional activity (Mhatre et al 1993, Chamberlain et al 1994, Jenster et al 1994, Nakajima et al 1996, Tut et al 1997, Irvine et al 2000, Callewaert et al 2003, Wang et al 2004. Conversely, a reduction in poly-Q length has been associated with a more active AR (Chamberlain et al 1994, Irvine et al 2000, Callewaert et al 2003, Wang et al 2004.…”

Section: Discussionmentioning

confidence: 99%

“…Expansion of the poly-Q repeat in the AR is proposed to lead to a receptor protein that is compromised for transcriptional activity (Mhatre et al 1993, Chamberlain et al 1994, Jenster et al 1994, Nakajima et al 1996, Tut et al 1997, Irvine et al 2000, Callewaert et al 2003, Wang et al 2004. Conversely, a reduction in poly-Q length has been associated with a more active AR (Chamberlain et al 1994, Irvine et al 2000, Callewaert et al 2003, Wang et al 2004. However, results from other studies have argued that transcriptional activity is not directly affected by poly-Q length, but that repeat expansion results in reduced receptor protein levels (Choong et al 1996, Neuschmid-Kaspar et al 1996, Brooks et al 1997.…”

Section: Discussionmentioning

confidence: 99%

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

Davies

Watt²,

Kelly

et al. 2008

Journal of Molecular Endocrinology

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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 (DQ) 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 a-helix structure, while deletion of the repeat resulted in a small loss of a-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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“…Our group showed that the presence of.shorter CAG and GGC repeats was observed in a high-risk group of African-American men, corroborating previous findings of a genetic component to prostate cancer predisposition. In the laboratory, shorter repeat size has been shown to result in increased activity of the receptor (Chamberlain et al, 1994;Irvine et al, 2000), and likewise complete deletion of the CAG repeat results in a receptor that is much more active than wild-type molecules (Callewaert et al, 2003). It is thus believed that the presence of the Q and G repeats provides inhibitory control over the AR NTD.…”

mentioning

confidence: 99%

Aberrant AR Signaling as a Function of Declining Androgen

Coetzee¹,

Pinski²

2006

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. SPONSOR/MONITOR'S REPORT NUMBER(S)12. DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThis is an Exploration -Hypothesis Development Award (EHD) in which we modeled in a mouse model system the natural androgen decline in the aging male (ADAM) as it occurs after the age of 40 years in humans. ADAM coincides with a dramatic increase in the prostate cancer incidence in all population groups. To date we have collected all biological specimens and are in the process of detailed analyses. We have also explored androgen receptor (AR) signaling in pilot studies to allow a better understanding of this axis in ADAM. COETZEE, Gerhard A. Annual progress report W81XWH-04-1-0049 COETZEE, Gerhard A. Annual progress report W81XWH-04-1-0049Introduction:The androgen receptor (AR), a ligand-dependent nuclear transcription factor, plays a vital role in prostate cancer (PCa) development by regulating the transcription of target genes involved in cell cycle regulation and apoptosis. Physician-induced androgen ablation (castration or AR inhibition) selects for aberrant AR signaling mechanisms in recurrent tumors that include AR and p160 cofactor overexpression and ligand-independent activation of the AR. The natural androgen decline in the aging Male (ADAM) occurs after the age of 40 years, which coincides with the dramatic increase in the prostate cancer incidence in all population groups.The viability of the following hypothesis is being evaluated: Prostate cancer progression to androgen independence with age is a consequence of ADAM. ADAM, in turn, selects for prostate cancer cell clones with hypersensitive AR signaling capabilities due to AR amplification, changes in cofactor expression profiles or non-steroidal activation of the AR. A novel outcome of this work may be the realization that inappropriate AR signaling contributes to PCa risk with age and that the AR is a legitimate target not only for prostate cancer treatments, but also possibly for prevention strategies via hormone replacement with advancing age. Body:A single hypothesis is being evaluated (see ab...

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Implications of a polyglutamine tract in the function of the human androgen receptor

Cited by 68 publications

References 26 publications

Mechanistic Relationship between Androgen Receptor Polyglutamine Tract Truncation and Androgen-dependent Transcriptional Hyperactivity in Prostate Cancer Cells

Mechanistic Relationship between Androgen Receptor Polyglutamine Tract Truncation and Androgen-dependent Transcriptional Hyperactivity in Prostate Cancer Cells

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

Aberrant AR Signaling as a Function of Declining Androgen

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