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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA084254-05
Application #
6777524
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Perry, Mary Ellen
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2004-08-20
Budget End
2005-06-30
Support Year
5
Fiscal Year
2004
Total Cost
$277,324
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Levine, Beth; Packer, Milton; Codogno, Patrice (2015) Development of autophagy inducers in clinical medicine. J Clin Invest 125:14-24
Wei, Yongjie; An, Zhenyi; Zou, Zhongju et al. (2015) The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation. Elife 4:
Wang, Hanzhi; Sun, Hui-Qiao; Zhu, Xiaohui et al. (2015) GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion. Proc Natl Acad Sci U S A 112:7015-20
Liu, Y; Levine, B (2015) Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ 22:367-76
An, Zhenyi; Tassa, Amina; Thomas, Collin et al. (2014) Autophagy is required for G?/G? quiescence in response to nitrogen starvation in Saccharomyces cerevisiae. Autophagy 10:1702-11
Wei, Yongjie; Zou, Zhongju; Becker, Nils et al. (2013) EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154:1269-84
Wang, Richard C; Wei, Yongjie; An, Zhenyi et al. (2012) Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338:956-9
Wang, Richard C; Levine, Beth (2011) Calcipotriol induces autophagy in HeLa cells and keratinocytes. J Invest Dermatol 131:990-3
Orvedahl, Anthony; Sumpter Jr, Rhea; Xiao, Guanghua et al. (2011) Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480:113-7
Bodemann, Brian O; Orvedahl, Anthony; Cheng, Tzuling et al. (2011) RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 144:253-67

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