Engineering of Specific Tissue Inhibitors to Block ADAM Type Metalloprotease-Mediated Mammary Neoplasia
Abstract
Breast cancers arise from the mis-regulated cell fate during the life span of mammary epithelial cells in growth, differentiation and death cycle. Among many genes controlling the cell fate, Notch gene (Int3), when over-activated, invariably leads to development of mouse mammary tumor. In Drosophila, Notch activation requires proteolytic processing by Kuzbanian, a member of membrane bound metalloprotease ADAM family. But does mKUZ direct the activation of Notch pathway in mammalian cells? What is the effect of inhibition of mKUZ in neoplastic transformation? Here, we report that mouse Kuzbanian (mKUZ) induced the expression of HES transcription and p38MAP kinase phosphorylation, which both are the down stream events triggered by Notch in Drosophila. mKUZ resided in cytoplasm, concentrated on the peri-nuclear region and associated with the cytosekeleton, consistent with that Notch activation occurs in the cytoplasm. Furthermore, we show that expression of dominant negative mutant of mKUZ lead to down regulation of wild type mKUZ, and rendered cells resistant to MYC induced cell transformation. Therefore, targeting the matrix metalloprotease mKUZ may prevent early neoplasia.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1999
- Accession Number
- ADB251763
Entities
People
- Yibing Yan
- Z. Werb
Organizations
- University of California, San Francisco