The process of autophagy, or bulk degradation of cellular proteins through an autophagosoic-lysosomal pathway, is important in normal growth control and may be defective in tumor cells. However, virtually nothing is known about mammalian genes that control autophagy and whether autophagy genes influence tumor development. Previously, the investigators discovered a novel Bcl-2-interacting gene, beclin 1, that maps to a tumor susceptibility locus on 17q21 and that shares structural similarity with the yeast autophagy gene, apg6/vps30. Their preliminary data indicates that beclin 1 promotes autophagy both in yeast and in mammalian cells, that beclin 1 suppresses mammary tumorigenesis, and that beclin 1 protein expression is down regulated in human breast cancer. Therefore, they postulate that beclin 1 provides a genetic link between autophagy and tumor suppressor pathways and that down-regulation of beclin 1 expression in malignant breast epithelium contributes to cancer development or progression. The overall aim of this proposal is to further understand the interrelationship between genetic control of autophagy and negative growth regulation through a focused structure-function analysis of beclin 1.
The specific aims are (1) to identify domains of beclin 1 required for autophagy, (2) to evaluate the interrelationship between autophagy function and tumor suppressor function of beclin 1, and (3) to identify functionally important binding partners for beclin 1 in mammalian autophagy/tumor suppressor pathways.
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