Apoptosis and autophagy are both genetically controlled cellular pathways that are involved in determining cell fate, tissue homeostasis, and development. Despite some clues about molecular links between the two pathways, the interrelationship between apoptosis and autophagy is poorly understood. Previously, we identified the mammalian autophagy protein, Beclin 1, that interacts with cellular anti-apoptotic proteins of the Bcl-2 family. In this grant, we propose to explore the functional significance of Beclin 1-Bcl-2 family member interactions with respect to the regulation of autophagy and apoptosis and the role of these interactions in C. elegans and mouse development. In the first specific aim, we will use yeast, C. elegans genetic and mammalian systems to investigate the hypothesis that Bcl-2 orthologs inhibit Beclin 1 ortholog dependent autophagy. We will evaluate whether such inhibition requires direct protein-protein interactions between Bcl-2 orthologs and Beclin 1 orthologs and whether the mechanism involves disruption of the Beclin 1-Class III PI3K complex-associated PI3 kinase activity. In the second specific aim, we will use C. elegans genetic and mammalian systems to investigate the hypothesis that Beclin 1 orthologs function primarily as survival genes that are required for the anti-apoptotic function of Bcl-2 orthologs. We will test whether the survival effects of Beclin 1 orthologs require protein-protein interactions with Bcl-2 orthologs and we will evaluate possible mechanisms by which Beclin 1 orthologs promote anti-death activity of Bcl-2 orthologs. Together, these studies will define the functional significance of interactions between the Bcl-2 anti-apoptotic proteins and Beclin 1 autophagy proteins. The results obtained are expected to help decipher the evolutionarily conserved interrelationships between apoptosis and autophagy pathways and to have important implications for understanding the normal developmental and the pathophysiological processes in which both apoptosis and autophagy occur.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109618-03
Application #
7122861
Study Section
Special Emphasis Panel (ZRG1-DEV-1 (01))
Program Officer
Spalholz, Barbara A
Project Start
2004-09-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$312,284
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
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Vega-Rubín-de-Celis, Silvia; Zou, Zhongju; Fernández, Álvaro F et al. (2018) Increased autophagy blocks HER2-mediated breast tumorigenesis. Proc Natl Acad Sci U S A 115:4176-4181
Fernández, Álvaro F; Sebti, Salwa; Wei, Yongjie et al. (2018) Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558:136-140
Bian, Ao; Shi, Mingjun; Flores, Brianna et al. (2017) Downregulation of autophagy is associated with severe ischemia-reperfusion-induced acute kidney injury in overexpressing C-reactive protein mice. PLoS One 12:e0181848
Sumpter Jr, Rhea; Levine, Beth (2017) Emerging functions of the Fanconi anemia pathway at a glance. J Cell Sci 130:2657-2662
Wei, Yongjie; Chiang, Wei-Chung; Sumpter Jr, Rhea et al. (2017) Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor. Cell 168:224-238.e10
Rocchi, Altea; Yamamoto, Soh; Ting, Tabitha et al. (2017) A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer's disease. PLoS Genet 13:e1006962
Galluzzi, Lorenzo; Bravo-San Pedro, José Manuel; Levine, Beth et al. (2017) Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov 16:487-511
Lee, Ming Y; Sumpter Jr, Rhea; Zou, Zhongju et al. (2017) Peroxisomal protein PEX13 functions in selective autophagy. EMBO Rep 18:48-60
Levine, Beth; Klionsky, Daniel J (2017) Autophagy wins the 2016 Nobel Prize in Physiology or Medicine: Breakthroughs in baker's yeast fuel advances in biomedical research. Proc Natl Acad Sci U S A 114:201-205

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