Cyclin G-associated kinase: A novel androgen receptor-interacting transcriptional coactivator that is overexpressed in hormone refractory prostate cancer
✍ Scribed by Mira R. Ray; Latif A. Wafa; Helen Cheng; Robert Snoek; Ladan Fazli; Martin Gleave; Paul S. Rennie
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- French
- Weight
- 518 KB
- Volume
- 118
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Abstract
The androgen receptor (AR), a steroid receptor family member, is a ligand‐dependent transcription factor that has an integral role in normal prostate development. Alterations in AR‐mediated activity can result in abnormal gene expression, dysregulated cell growth and prostate cancer. Coregulator proteins that interact with AR to influence activity and specificity of the AR‐response may also have an important role in prostate cancer progression. Since the NH~2~‐terminal domain (NTD) of AR encodes the ligand‐independent activation function (AF)‐1, this domain is incompatible with conventional yeast two‐hybrid systems. Therefore, we have used the Tup1 repressed transactivator (RTA) system, which exploits the intrinsic transactivation properties of AR.NTD, for identification of novel AR‐interacting proteins. Using this system, cyclin G‐associated kinase (GAK) was identified as an AR interacting protein, and GST pull‐down assays were used to confirm the interaction. GAK was shown to enhance the AF‐1 function of AR activity in a ligand‐dependent manner. Additionally, GAK enhanced the AR transcriptional response even at low concentrations of androgens, which is relevant to AR activity in androgen‐independent prostate cancer. Finally, neo‐adjuvant hormone therapy (NHT) tissue microarray analysis demonstrated that GAK expression increased significantly with prostate cancer progression to androgen independence, which suggests a prognostic role for GAK in advanced disease. © 2005 Wiley‐Liss, Inc.