The Rap-1 Antioncogene in Breast Cancer.
Abstract
This project aims to devise strategies to antagonize the promitogenic action of Ras and thereby suppress the transforming activity of the Erb B2 oncogenes found in 70% of human breast adenocarcinomas. The initial strategy was based on the ability of the Rap-1 GTPase when overexpressed, to suppress the malignant phenotype of V12 Ras transformed fibroblasts. It was anticipated that Rap-1 which shares an identical sequence corresponding to the primary Ras effector binding domain (amino acids (32-44), when overexpressed competes with Ras for critical mitogenic effects. In the past year, we have focused on the identification and characterization of proteins that interact with Rap-1 and Ras through their effector loop, in a GIP dependent fashion. We are attempting to ascertain whether the several proteins we have isolated that exhibit effector loop dependent binding to Rap-1 and Ras actually function as effectors for either Rap-1 or Ras, and whether they participate in regulation of the mitogenic activity of the cell in a positive or negative fashion. We have initially characterized the protein AF-6 because it was first isolated as a fusion partner of gene ALL-1, a chromosomal translocation found in acute leukemias. AF-6 binds to Ras and Rap-1 in a GTP dependent fashion, with a higher affinity for Rap-1. This contrasts with Raf, which prefers Ras. Future work will examine the ability of AF-6 and other candidate effectors to alter cell growth.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1996
- Accession Number
- ADA321768
Entities
People
- Joseph Avruch
Organizations
- Massachusetts General Hospital