Molecular Analysis of Bcl-xs-Induced Apoptosis in Breast Cancer.
Annual rept. 1 Jul 97-30 Jun 98
MICHIGAN UNIV ANN ARBOR SCHOOL OF MEDICINE
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A major genetic event that occurs in the pathogenesis of breast carcinoma involves alterations in the Bcl-2 survival pathway. To determine the role of the Bcl-2 family in maintaining cancer cell viability, we constructed a recombinant adenovirus vector that expresses Bcl-xs, a dominant inhibitor of these proteins. In the original proposal, we proposed studies to determine the mechanism involved in Bcl-xs-mediated apoptosis, to characterize cellular proteins that interact with Bcl-xs using biochemical and genetic approaches, and to use a transgenic model of Bcl-xs expression in the breast to assess the requirement for Bcl-2Bcl-xL in the maintenance of normal breast epithelia and tumor growth. During the last two years, we have characterized the interaction of Bcl-xs with Bcl-2 and Bcl-xL and identified through a genetic screen, HRK, a novel protein that interacts with Bcl-2 and Bcl-xL. Mutational analysis of Bcl-xs revealed a conserved region of this protein that is important for interaction with Bcl-xL and induction of apoptosis. Bcl-xL and Bcl-xs were found to associate with Apaf-1, a critical regulator of caspases and cell death, suggesting that Bcl-xs might antagonize Bcl-xL through Apaf-1. Finally, transgenic mice expressing Bcl-xs in the breast have been developed and partially characterized.
- Anatomy and Physiology
- Medicine and Medical Research