Use p27(KIPI) Degradation for Breast Cancer Diagnosis and Therapy
Abstract
The goal of this research is to determine whether inhibition of the ubiquitin-dependent degradation of the CDK inhibitor p27(Kipl) can be used for inhibiting the growth of breast cancer cells and whether it can be used as a potential target of breast cancer therapy. Low or absent expression of p27 is associated with poor prognosis for breast cancer patients. We have identified the SCF(SKP2) complex as the E3 ligase that targets p27 for ubiquitin-dependent proteolysis. To determine whether SCF(SKP2) serves as a target for breast cancer therapy, we have characterized the binding of SKP2, the substrate-targeting subunit of SCF(SKP2), to p27 and found that the carboxy-terminal region of SKP2 binds to phosphorylated p27 substrate and thus define the substrate-specificity. Ablation of SKP2 by RNA interference is sufficient to inhibit p27 degradation, resulting in the p27 accumulation and cell cycle arrest in breast cancer cells. We have also isolated an inhibitor of SCF(SKP2), p120(CAND1), and found that its expression causes p27 accumulation and inhibits cell cycle progression. Thus we conclude that inhibition of the SCF(SKP2)-dependent p27 proteolysis is sufficient to inhibit the growth of breast cancer cells and blocking the p27 degradation provides a novel strategy for breast cancer therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA425186
Entities
People
- Hui Zhang
Organizations
- Yale University