Vav3, a Rho GTPase guanine nucleotide exchange factor, increases during progression to androgen independence in prostate cancer cells and potentiates androgen receptor transcriptional activity.
The progression of prostate cancer from androgen dependence to androgen independence is often accompanied by enhanced androgen receptor (AR) transcriptional activity. We observed a marked increase in the expression of Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), during the progression of human prostate cancer LNCaP cells to the androgen-independent derivative, LNCaP-R1. GEFs activate Rho family GTPases by promoting the exchange of GDP for GTP. Reporter gene assays showed that Vav3 potentiated AR transcriptional activity, and knock down of Vav3 resulted in decreased AR transactivation. Vav3 also increased androgen-induced levels of prostate-specific antigen mRNA. Furthermore, Vav3 enhanced AR activity at subnanomolar concentrations of androgen. This finding is particularly relevant because low androgen levels may be present in prostate tissue of patients undergoing androgen deprivation therapy. Enhancement of AR activity by Vav3 required amino terminal activation function 1 (AF1) of AR; however, Vav3 did not interact with AR or increase AR levels. Neither GEF function nor the C-terminal domains of Vav3 were required for Vav3-mediated enhancement of AR activity; however, the pleckstrin homology domain was obligatory. These data show that Vav3 levels rise during progression to androgen independence and support continued AR signaling (even under conditions of low androgen) by a novel GEF-independent cross-talk mechanism.
Lyons
Leah S
LS
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, 1600 Northwest 10th Avenue, Miami, Florida 33136, USA.
Burnstein
Kerry L
KL
D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
D000728:Androgens; D020662:Guanine Nucleotide Exchange Factors; D051567:Proto-Oncogene Proteins c-vav; D012333:RNA, Messenger; D011944:Receptors, Androgen; C496621:VAV3 protein, human; D019869:Phosphatidylinositol 3-Kinases; D017430:Prostate-Specific Antigen