Transcriptional regulation of the androgen receptor cofactor androgen receptor trapped clone-27

Jerome C. Nwachukwu, Wenhui Li, Inés Pineda-Torra, Ying Huang Hong, Rachel Ruoff, Ellen Shapiro, Samir S. Taneja, Susan K. Logan, Michael J. Garabedian

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Cofactors modulate nuclear receptor activity and impact human health and disease, yet surprisingly little is known about their transcriptional regulation. Androgen receptor trapped clone-27 (ART-27) is a cofactor that binds to androgen receptor (AR) amino terminus and modulates AR-dependent transcription. Interestingly, ART-27 displays both a cell type- and developmental stage-specific expression pattern. However, the cis-acting elements and trans-acting factors affecting ART-27 gene expression have not been elucidated. We found that ART-27 gene expression is repressed and its promoter is histone H3-K27 tri-methylated in human embryonic kidney cells, but not prostate cells, and the histone deacetylase inhibitor, trichostatin A, relieves this inhibition. The DNA response elements that control the induction of ART-27 gene expression were also characterized. The major cis-acting element corresponds to a consensus cAMP-responsive element (CRE) and binds the CRE-binding protein (CREB) as shown by EMSA and chromatin immunoprecipitation assays. Furthermore, ART-27 promoter activity is induced upon CREB overexpression. Epidermal growth factor, which activates CREB via phosphorylation, also induces ART-27 expression, whereas a reduction in CREB phosphorylation or expression blocks this induction in prostate cells. In human prostate development, both epithelial and stromal cells express CREB; however, active phosphorylated CREB is restricted to epithelial cells where ART-27 is expressed. Based on these findings, we propose a transcriptional regulatory circuit for the developmental expression of ART-27 that includes repression by chromatin modification through a trichostatin A-sensitive factor and activation upon growth factor stimulation via CREB.

Original languageEnglish (US)
Pages (from-to)2864-2876
Number of pages13
JournalMolecular Endocrinology
Volume21
Issue number12
DOIs
StatePublished - Dec 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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