Cyclin G-associated kinase: a novel androgen receptor-interacting transcriptional coactivator that is overexpressed in hormone refractory prostate cancer

Int J Cancer. 2006 Mar 1;118(5):1108-19. doi: 10.1002/ijc.21469.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / therapeutic use*
  • Cell Line, Tumor
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Disease Progression
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism
  • Tissue Array Analysis
  • Transcriptional Activation / genetics


  • Androgens
  • Cyclins
  • IFNGR2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Androgen
  • Receptors, Interferon
  • GAK protein, human
  • Protein Serine-Threonine Kinases