Roles of Mitotic Checkpoint Regulators Pin1 and Pin2 in Breast Cancer
Abstract
Our laboratory has recently identified a new protein, Pinl, that is involved in checkpoint control. Pinl interacts with mitotic phosphoproteins and helps to orchestrate the timing of mitotic events. We found that Pin1 is highly overexpressed in breast cancer. Pinl levels correlate with the levels of cyclin Dl protein as well as with cyclin Dl mRNA levels in human breast tumors. We have shown that Pin1 is a transcriptional activator of cyclin Dl. Activation occurs indirectly through the binding of phosphorylated c-jun. Our data indicate that Pinl may contribute to neoplastic transformation by causing accumulation of cyclin Dl. In addition, Pinl contributes to cyclin Dl overexpression by regulating the turnover and subcellular localization of beta-catenin and inhibiting its interaction with APC. In Pinl knock-out mice, mammary epithelial cells fail to undergo the usual proliferative burst during pregnancy, a phenotype that is very similar to the cyclin Dl knock-out. Finally, the PINl gene itself is an E2F target gene and essential for Neu/Ras induced transformation of mammary epithelial cells. Crossbreeding experiments have shown that Pinl knock-out mice are largely protected from breast cancers induced by the Her2/neu or Ras oncogenes.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA424006
Entities
People
- Gerburg M Wulf
- Kun P. Lu
Organizations
- Beth Israel Deaconess Medical Center