Role of Cdc37 in Overcoming p16 Mediated Growth Arrest in Prostate Cancer
Abstract
Cdc37 is a co-chaperone protein that recruits several immature client kinases to Hsp90 for proper folding. Cdc37 up-regulation is a common early event in localized prostate cancer as is p16 induction. While targeted overexpression in mice leads to prostate epithelial cell hyperplasia, the function of Cdc37 in human prostate cancer is unclear. Here I examine the role of Cdc37 in the growth regulation of prostate cells. Using laser capture microdissection, Cdc37 and p16 are both concomitantly induced in moderately differentiated prostate cancer tissue. However, Cdc37 overexpression was unable to overcome p16 induced growth arrest in prostate cancer cells. I demonstrate that Cdc37 overexpression drives proliferation in normal prostate epithelial cells, while loss of Cdc37 function arrests growth and leads to apoptosis. Molecular analysis of Cdc37 client pathways indicated enhanced Raf-1 activity, up-regulated Cdk4 levels and reduced p16 expression with Cdc37 overexpression. These findings suggest increased Raf-1 and/or Cdk4 activity might underlie the proliferative enhancement. Induced Raf-1 activation, however, slowed growth, while cyclin Dl overexpression was sufficient to promote proliferation. These data farther suggest that Cdc37 may play an active role in the progression of prostate cancer through accelerating proliferation and preventing apoptosis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2003
- Accession Number
- ADA414677
Entities
People
- Steven R. Schwarze
Organizations
- University of Wisconsin–Madison