A Unifying Theory of Prostate Cancer
Abstract
The goal of this project was to investigate the biological behavior of p53 in primary cultures of human prostatic epithelial cells. Previous studies had revealed that p53 was not activated in these cells by agents that cause double-stranded DNA breaks, such as gamma-irradiation, suggesting that p53, albeit wild-type, was dysfunctional. Since p53 is a key tumor suppressor gene that protects the genome from damage, we hypothesized that dysfunctional p53 is relevant to the high incidence of cancer in the prostate. In order to determine whether p53 was irreversibly nonfunctional in prostate cells, we inhibited RNA transcription or nuclear protein export. In response, p53 protein accumulated and was functional, as evidenced by transactivation of downstream targets and cell cycle arrest. Therefore, mechanisms responsible for up-regulation and activation of p53 are intact in prostatic epithelial cells. We also determined that p53 was activated by ultraviolet radiation, which creates bulky DNA adducts, and by triptolide, a drug whose mechanism of action has not yet been elucidated. These findings show that certain pathways of p53 activation are functional in prostate cells, and that the defect lies in a specific inability of the cells to protect themselves from double-stranded DNA breaks. This finding is relevant to the initiation, progression and therapy of prostate cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADB282244
Entities
People
- Donna Peehl
Organizations
- Stanford University