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Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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Transcriptional regulation of the androgen receptor cofactor androgen receptor trapped clone-27

Jerome C Nwachukwu1, Wenhui Li, Inés Pineda-Torra

  • 1Department of Microbiology, 550 First Avenue, New York, New York 10016, USA.

Molecular Endocrinology (Baltimore, Md.)
|September 1, 2007
PubMed

Insights

Androgen receptor trapped clone-27 (ART-27) gene expression is regulated by chromatin modification and the CREB protein. Growth factors like EGF activate CREB, inducing ART-27 expression, particularly in prostate epithelial cells.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Gene Regulation

Background:

  • Nuclear receptor cofactors significantly influence human health and disease, yet their transcriptional regulation remains poorly understood.
  • Androgen receptor trapped clone-27 (ART-27) is a cofactor that modulates androgen receptor (AR)-dependent transcription and exhibits cell type- and developmental stage-specific expression.
  • The specific cis-acting elements and trans-acting factors governing ART-27 gene expression have not been previously identified.

Purpose of the Study:

  • To elucidate the transcriptional regulatory mechanisms controlling ART-27 gene expression.
  • To identify the cis-acting elements and trans-acting factors involved in ART-27 gene regulation.
  • To understand the role of chromatin modification and growth factor signaling in ART-27 expression.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assays to identify protein-DNA interactions.
  • Electrophoretic mobility shift assays (EMSA) to study protein binding to DNA elements.
  • Reporter gene assays to assess promoter activity upon manipulation of regulatory factors.
  • Treatment with histone deacetylase inhibitors (e.g., trichostatin A) and growth factors (e.g., EGF).

Main Results:

  • ART-27 gene expression is repressed in human embryonic kidney cells via histone H3-K27 trimethylation, a state reversed by trichostatin A.
  • A key cis-acting element in the ART-27 promoter is a cAMP-responsive element (CRE) that binds the CRE-binding protein (CREB).
  • ART-27 promoter activity is induced by CREB overexpression and epidermal growth factor (EGF) stimulation, which activates CREB phosphorylation. This induction is blocked by reduced CREB phosphorylation or expression.
  • During human prostate development, phosphorylated CREB and ART-27 expression are localized to epithelial cells.

Conclusions:

  • ART-27 gene expression is controlled by a dual mechanism involving repression via trichostatin A-sensitive chromatin modification and activation through growth factor-mediated CREB signaling.
  • The findings reveal a transcriptional regulatory circuit for ART-27, highlighting the importance of CREB in its developmental expression, particularly in prostate epithelial cells.
  • This study provides novel insights into the complex regulation of nuclear receptor cofactors and their role in development and potentially disease.

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