Role of ART-27, a Novel Androgen Receptor Coactivator, in Normal Prostate and Prostate Cancer.

摘要

Androgen receptor (AR), a hormone-dependent transcription factor, plays a role in the growth of normal and malignant prostate cells. Androgen Receptor Trapped clone-27 (ART-27), a recently identified AR N-terminal coactivator, may interact with the receptor modulating its activity and affecting cell growth. Here we examined the effect of 13 naturally occurring AR N-terminal mutations on the transcriptional response of the receptor to ART-27. It was found that, one of these mutation, AR P340L, a somatic alteration associated with prostate cancer, although interact more avidly with ART27, paradoxically decreases AR transcription. This may represent a novel mechanism of pathogenesis whereby increased AR-coactivator association negatively regulates AR activity and biological response. Previous studies have shown ART- 27 is expressed in normal adult human prostate in the luminal epithelial cells but not in the undifferentiated precursor cells, and is negligibly expressed in prostate cancer. Understanding the regulation of ART-27 gene transcription will help us to elucidate the role of ART-27 in prostate and the cancer development. We hence have mapped ART-27 promoter region and identified a minimal cis- element with a strong basal activity and its likely binding factor CREB/ATF. Functional significance of CREB/ATF in ART-27 regulation will be under further investigation.