Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer.
Growth of normal and neoplastic prostate is mediated by the androgen receptor (AR), a ligand-dependent transcription factor activated by high affinity androgen binding. The AR is highly expressed in recurrent prostate cancer cells that proliferate despite reduced circulating androgen. In this report, we show that epidermal growth factor (EGF) increases androgen-dependent AR transactivation in the recurrent prostate cancer cell line CWR-R1 through a mechanism that involves a post-transcriptional increase in the p160 coactivator transcriptional intermediary factor 2/glucocorticoid receptor interacting protein 1 (TIF2/GRIP1). Site-specific mutagenesis and selective MAPK inhibitors linked the EGF-induced increase in AR transactivation to phosphorylation of TIF2/GRIP1. EGF signaling increased the coimmunoprecipitation of TIF2 and AR. AR transactivation and its stimulation by EGF were reduced by small interfering RNA inhibition of TIF2/GRIP1 expression. The data indicate that EGF signaling through MAPK increases TIF2/GRIP1 coactivation of AR transactivation in recurrent prostate cancer.
Gregory
Christopher W
CW
Laboratories for Reproductive Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599-7500, USA.
Fei
Xiaoyin
X
Ponguta
Liliana A
LA
He
Bin
B
Bill
Heather M
HM
French
Frank S
FS
Wilson
Elizabeth M
EM
D000818:Animals; D015152:Blotting, Northern; D019556:COS Cells; D002455:Cell Division; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009368:Neoplasm Transplantation; D051958:Nuclear Receptor Coactivator 2; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
D008024:Ligands; C498001:NCOA2 protein, human; C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D011944:Receptors, Androgen; D014157:Transcription Factors; D004815:Epidermal Growth Factor