Cdc37 is a co-chaperone protein that recruits several immature client<lb>kinases to Hsp90 for proper folding. Cdc37 up-regulation is a common<lb>early event in localized human prostate cancer. Although targeted over-<lb>expression in mice leads to prostate epithelial cell hyperplasia, the effect of<lb>Cdc37 dysregulation in human prostate cells is unclear. In this study, we<lb>examine the role of Cdc37 in the grovrth regulation of normal prostate<lb>epithelial cells using a unique human model system. We demonstrate that<lb>Cdc37 overexpression drives proliferation, whereas loss of Cdc37 function<lb>arrests growth and leads to apoptosis. With increased Cdc37 expression,<lb>molecular analysis of Cdc37 client pathways demonstrates enhanced<lb>Raf-1 activity, greater Cdk4 levels, and reduced expression of the cyclin-<lb>dependent kinase inhibitor pl6/CDKN2. To further investigate these<lb>downstream pathways, enhanced Raf-1 or Cdk4 activities were selectively<lb>induced in human prostate epithelial cells. Raf-1 activation inhibited<lb>proliferation and generated an enlarged, flattened morphology. Induction<lb>of Cdk4 activity using cyclin Dl overexpression, however, was sufficient to<lb>promote proliferation. These data indicate that Cdc37 induces prolifera-<lb>tion and is critical for survival in human prostate epithelial cells. These<lb>alterations in cell division and survival may be important in the develop-<lb>ment and progression of early prostate cancer.