Targeting of Oncogenic Proteins for Intracellular Degradation
Abstract
Selective depletion of intracellular oncogenic proteins is a potentially powerful tool for the treatment of breast cancer. This is usually achieved by genetic manipulation of the target gene using procedures such as gene disruption, antisense or ribozyme technologies. We now propose an alternative approach in which an oncogenic protein is specifically targeted for intracellular degradation. In order to do this we will take advantage of the permeability properties of the third helix of the antennapedia protein. This will be used to deliver a small trifunctional peptide consisting of a target protein binding peptide and a peptide designed to interact with the E2 class of ubiquitin conjugating enzymes. In this way the ubiquitin-conjugating machinery will be selectively recruited to the target protein which should then be degraded by the proteosome. We will use the cytoplasmic signaling molecule (3-catenin as a model system since its oncogenic activity is thought to be regulated at the level of protein stability and we have established that it is normally targeted for ubiquitination and proteosomal degradation. Mutations of Beta-catenin which increase its protein stability are oncogenic. The Beta-catenin binding peptide will be based on the region of the tumor suppressor protein APC which constitutively binds Beta-catenin.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA386498
Entities
People
- Stephen Byers
Organizations
- Georgetown University