The Rap-1 Antioncogene in Breast Cancer.
Annual rept. 29 Aug 94-28 Aug 95,
MASSACHUSETTS GENERAL HOSPITAL BOSTON
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This project aims to understand the biologic functions of the small GTPase Rap-1, the mechanism by which overexpression or overactivation of Rap-1 can antagonize the promitogenic actions of Ras, and to determine whether strategies can be devised to recruit this antioncogenic function of Rap-1 to treat breast cancer. Initial studies using a high affinity polyclonal antibody specific for Rap-1 indicate that Rap-1 is expressed in many cell lines, including the MCF-7 breast cancer line. Preliminary studies in Rat-1 cells indicate that endogenous Rap-1 may associate with the Raf-1 protooncogene in situ in a regulated fashion Raf-1 is a critical mitogenic effector of the Ras protooncogene. The effect of Rap-1 association on the activation of the Raf-1 kinase and the downstream MAP kinase cascade is not yet known. Expression cloning of Rap-1 interacting proteins has yielded a large number of Raf-1 sequences, many isoforms of guanyl nucleotide exchange proteins for other small GTPases, and a variety of proteins of unknown function several of the latter are multiply represented, and contain interesting regulatory domains, but lack unmistakable catalytic domains. The role of these polypeptides in Rap-1s biologic program and potential antioncogenic action remains to be uncovered. Future studies will define more fully the interactions of Rap and Raf in situ, the regulation of this coupling and the significance to Rafs mitogenic signalling.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research