Structural Characterization of a Novel HER2/neu Binding Ets Factor, ESX
Annual rept. 1 Jul 1998-30 Jun 1999
CALIFORNIA UNIV SAN FRANCISCO
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Overexpression of the HER2neu proto-oncogene in breast cancer occurs in approximately 20 of cases and is related to poor patient prognosis. An improved understanding of how the HER2 proto-oncogene is regulated at the level of transcription would be beneficial for the rational design of therapeutic strategies aimed at reducing HER2 receptor expression. We have described and cloned a new Ets transcription factor, ESX, and shown that it binds to the Ets response element of the HER2 promoter GAGGAA, where it causes upregulation of HER2 transcription. Elucidation of the three dimensional structure of ESX bound to the HER2 promoter is critical for development of novel therapeutics to block ESX transactivating function. We propose to determine crystallographic structures of defined protein domains of the multi-domain Ets transcription factor ESX alone and in complex with the HER2 promoter element. The ultimate goal of this research is to use structural analysis to define inter-domain interactions of ESX or specific contacts between ESX and the HER2neu promoter, which can later be targeted for the design of small molecule modulators of ESX transactivating function. To this end we have expressed, purified and initiated crystal screens of full-length ESX and four peptides. Additional constructs of ESX will be tried, since to date no crystals have grown.
- Anatomy and Physiology
- Medicine and Medical Research