c-Jun has multiple enhancing activities in the novel cross talk between the androgen receptor and Ets variant gene 1 in prostate cancer.
The multiple transcriptional roles of c-Jun are shown in a novel cross-talk between the androgen receptor (AR) and its new target gene, Ets variant gene 1 (ETV1). In this report, we show that c-Jun can mediate AR induction of ETV1 expression independent of c-Jun transactivation function. Interestingly, c-Jun can transactivate the cloned ETV1 promoter also in the absence of ligand-activated AR, suggesting two mechanisms by which c-Jun can induce ETV1 expression. In addition, both wild-type c-Jun and a transactivation-deficient mutant can enhance the transcriptional activity of ETV1, as measured by both reporter gene assay and endogenous expression of matrix metalloproteinase genes, well-known targets of Ets proteins. Overexpression of the c-Jun mutant protein also led to increased prostate cancer cell invasion. Immunoprecipitation and immunocytochemistry experiments showed copurification and colocalization of c-Jun with AR or ETV1, suggesting that c-Jun acts on AR or ETV1 via a physical association. Collectively, these results, together with a parallel overexpression of ETV1, c-Jun, and AR in prostate tumors, imply that c-Jun plays a pivotal role in the pathway that connects ligand-activated AR to elevated ETV1 expression, leading to enhanced expression of matrix metalloproteinases and prostate cancer cell invasion.
Cai
Changmeng
C
Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA.
Hsieh
Chen-Lin
CL
Shemshedini
Lirim
L
D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics; D046228:Microarray Analysis; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured
C410798:AR protein, human; D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; D016755:Proto-Oncogene Proteins c-jun; D011944:Receptors, Androgen; D014157:Transcription Factors; D020782:Matrix Metalloproteinases