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

Qianben Wang, Thirupandiyur Udayakumar, Tadas S. Vasaitis, Angela M. Brodie, Joseph D. Fondell

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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 NH2- 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.

Original languageEnglish (US)
Pages (from-to)17319-17328
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number17
DOIs
StatePublished - Apr 23 2004
Externally publishedYes

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Androgen Receptors
Androgens
Prostatic Neoplasms
Cells
Ligands
polyglutamine
Critical Pathways
Chromatin Assembly and Disassembly
Transcription
Chromatin
Prostate
Proteins
Genes
Cell Proliferation
DNA
Growth

ASJC Scopus subject areas

  • Biochemistry

Cite this

Mechanistic Relationship between Androgen Receptor Polyglutamine Tract Truncation and Androgen-dependent Transcriptional Hyperactivity in Prostate Cancer Cells. / Wang, Qianben; Udayakumar, Thirupandiyur; Vasaitis, Tadas S.; Brodie, Angela M.; Fondell, Joseph D.

In: Journal of Biological Chemistry, Vol. 279, No. 17, 23.04.2004, p. 17319-17328.

Research output: Contribution to journalArticle

Wang, Qianben ; Udayakumar, Thirupandiyur ; Vasaitis, Tadas S. ; Brodie, Angela M. ; Fondell, Joseph D. / Mechanistic Relationship between Androgen Receptor Polyglutamine Tract Truncation and Androgen-dependent Transcriptional Hyperactivity in Prostate Cancer Cells. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 17. pp. 17319-17328.
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