A signaling network in phenylephrine-induced benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is an age-related disease of unknown etiology characterized by prostatic enlargement and coinciding with distinctive alterations in tissue histomorphology. To identify the molecular mechanisms underlying the development of BPH, we conducted a DNA microarray study using a previously described animal model in which chronic alpha(1)-adrenergic stimulation by repeated administration of phenylephrine evokes histomorphological changes in the rat prostate that resemble human BPH. Bioinformatic tools were applied to microarray data obtained from prostate tissue to construct a network model of potentially relevant signal transduction pathways. Significant involvement of inflammatory pathways was demonstrable, including evidence for activation of a TGF-beta signaling cascade. The heterodimeric protein clusterin (apolipoprotein J) was also identified as a prominent node in the network. Responsiveness of TGF-beta signaling and clusterin gene and protein expression were confirmed independently of the microarray data, verifying some components of the model. This is the first attempt to develop a comprehensive molecular network for histological BPH induced by adrenergic activation. The study also implicated clusterin as a novel biochemical target for therapy.
Kim
Jayoung
J
Departments of Surgery andBiological Chemistry and Molecular Pharmacology, Harvard Medical School, The Urological Diseases Research Center, Children's Hospital, Boston, Massachusetts 02115, USA. michael.freeman@childrens.harvard.edu
Yanagihara
Yutaka
Y
Kikugawa
Tadahiko
T
Ji
Mihee
M
Tanji
Nozomu
N
Masayoshi
Yokoyama
Y
Freeman
Michael R
MR
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011470:Prostatic Hyperplasia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics
D000316:Adrenergic alpha-Agonists; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D016212:Transforming Growth Factor beta; D010656:Phenylephrine