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This Article Full Text Full Text (PDF) All Versions of this Article: 73/5/951    most recent biolreprod.105.040980v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal My Folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mukai, M. Articles by Cooke, P. S. Search for Related Content PubMed PubMed Citation Articles by Mukai, M. Articles by Cooke, P. S. Agricola Articles by Mukai, M. Articles by Cooke, P. S.

Altered Prostatic Epithelial Proliferation and Apoptosis, Prostatic Development, and Serum Testosterone in Mice Lacking Cyclin-Dependent Kinase Inhibitors¹

Department of Veterinary Biosciences,³ University of Illinois, Urbana, Illinois 61802 Population Council and Rockefeller University,⁴ New York, New York 10021 Department of Molecular Genetics,⁵ College of Medicine, University of Illinois, Chicago, Illinois 60607 School of Pharmacy,⁶ University of Wisconsin, Madison, Wisconsin 53705

Normal prostatic development and some prostatic diseases involve altered expression of the cell-cycle regulators p27 and p21 (also known as CDKN1B and CDKN1A, respectively). To determine the role of these proteins in the prostate, we examined prostatic phenotype and development in mice lacking p27 and/or p21. In p27-knockout (p27KO) mice, epithelial proliferation was increased 2- and 3.8-fold in the ventral and dorsolateral prostate, respectively, versus wild-type (WT) mice, although prostatic weights were not different. Epithelial apoptosis was increased in p27KO mice and may account for the lack of a concurrent increase in weight. Testosterone deficiency observed in this group was not the cause of this increase, because vehicle- and testosterone-treated p27KO mice had similar percentages of apoptotic cells. Also observed was a trend toward a decreased functional epithelial cytodifferentiation, indicating a potential role of p27 in this process. Conversely, dorsolateral prostate and seminal vesicle (SV) of p21-knockout (p21KO) mice, and all prostatic lobes and SV of p21/p27 double-knockout mice, weighed significantly less compared to the WT mice, and their epithelial proliferation was normal. Decreased testosterone concentrations may contribute to the decreased prostatic weights. However, other factors may be involved, because testosterone replacement only partially restored prostatic weights. We conclude that loss of p27 increases prostatic epithelial proliferation and alters differentiation but does not result in prostatic hyperplasia because of increased epithelial cell loss. The p21KO mice showed phenotypes distinctly different from those of p27KO mice, suggesting nonredundant roles of p21 and p27 in prostatic development. Loss of p27 or of both p21 and p27 results in serum testosterone deficiency, complicating analysis of the prostatic effects of these cell-cycle regulators.

apoptosis, male reproductive tract, prostate, testosterone