Identification of genetic pathways activated by the androgen receptor during the induction of proliferation in the ventral prostate gland.
The androgen receptor (AR), when complexed with 5alpha-dihydrotestosterone (DHT), supports the survival and proliferation of prostate cells, a process critical for normal development, benign prostatic hypertrophy, and tumorigenesis. However, the androgen-responsive genetic pathways that control prostate cell division and differentiation are largely unknown. To identify such pathways, we examined gene expression in the ventral prostate 6 and 24 h after DHT administration to androgen-depleted rats. 234 transcripts were expressed significantly differently from controls (p < 0.05) at both time points and were subjected to extensive data mining. Functional clustering of the data reveals that the majority of these genes can be classified as participating in induction of secretory activity, metabolic activation, and intracellular signaling/signal transduction, indicating that AR rapidly modulates the expression of genes involved in proliferation and differentiation in the prostate. Notably AR represses the expression of several key cell cycle inhibitors, while modulating members of the wnt and notch signaling pathways, multiple growth factors, and peptide hormone signaling systems, and genes involved in MAP kinase and calcium signaling. Analysis of these data also suggested that p53 activity is negatively regulated by AR activation even though p53 RNA was unchanged. Experiments in LNCaP prostate cancer cells reveal that AR inhibits p53 protein accumulation in the nucleus, providing a post-transcriptional mechanism by which androgens control prostate cell growth and survival. In summary these data provide a comprehensive view of the earliest events in AR-mediated prostate cell proliferation in vivo, and suggest that nuclear exclusion of p53 is a critical step in prostate growth.
Nantermet
Pascale V
PV
Department of Molecular Endocrinology and Bone Biology, Merck Research Laboratories, West Point, PA 19486, USA.
Xu
Jian
J
Yu
Yuanjiang
Y
Hodor
Paul
P
Holder
Daniel
D
Adamski
Sharon
S
Gentile
Michael A
MA
Kimmel
Donald B
DB
Harada
Shun-Ichi
S
Gerhold
David
D
Freedman
Leonard P
LP
Ray
William J
WJ
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D019295:Computational Biology; D018076:DNA, Complementary / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D005786:Gene Expression Regulation; D008297:Male; D008856:Microscopy, Fluorescence; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000737:chemistry; D011467:Prostate / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000728:Androgens; D018076:DNA, Complementary; D010455:Peptides; D012333:RNA, Messenger; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; D013196:Dihydrotestosterone