Cell proliferation and expression of cell cycle regulatory proteins that control the G1/S transition are age dependent and lobe specific in the Brown Norway rat model of prostatic hyperplasia.
Age-dependent epithelial cell hyperplasia in the dorsal and lateral lobes of Brown Norway rats is analogous to benign prostatic hyperplasia in aging men. A major question is whether differential lobe-specific and age-dependent proliferation of cells, rather than cell survival, contributes to the hyperplasia. Although serum testosterone (T) levels decline in aged rats, active cell proliferation was detected as Ki67-positive cells in the dorsal and lateral lobes. We determined whether androgens differentially affect cell proliferation and cell-cycle regulatory proteins in the prostate lobes of young and aged rats. Castrated rats were treated with different doses of T to restore serum levels to those of intact young or aged rats. Rates of cell proliferation, measured by 5-bromodeoxyuridine labeling, peaked after 3-d T treatment in all lobes. 5-bromodeoxyuridine-labeling indices were higher in the dorsal and lateral lobes of aged than of young rats with equivalent serum T levels. No age-dependent difference was seen in the ventral lobe. Cell proliferation was marked by increased levels of cyclins D1 and E and cyclin-dependent kinases 4 and 6, decreased p27 and increased phosphorylation of Rb. Levels of cyclins D1 and E were higher in the dorsal and lateral lobes of intact and T-treated aged than young rats. Confocal immunofluorescent microscopy documented changes in cyclin-dependent kinase 4 and cyclin D1 subcellular localization. Cyclin D1 nuclear localization correlated with the time frame for cell proliferation. In conclusion, rates of cell proliferation and levels of cell-cycle regulatory proteins that control the G1/S transition exhibit lobe-specific and age-dependent differences in response to androgens.
Yan
Jinchun
J
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Room W3606, 615 North Wolfe Street, Baltimore, Maryland 21205-2103, USA.
Brown
Terry R
TR
D000367:Age Factors; D000818:Animals; D002369:Castration; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D016193:G1 Phase / Q000235:genetics*; D005786:Gene Expression Regulation; D008297:Male; D009929:Organ Size; D009928:Organ Specificity; D011467:Prostate / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011914:Rats, Inbred BN; D016196:S Phase / Q000235:genetics*; D013739:Testosterone / Q000097:blood; D014018:Tissue Distribution
D018797:Cell Cycle Proteins; D019938:Cyclin D1; D013739:Testosterone; D051358:Cyclin-Dependent Kinase 4