Autophagy is a conserved catabolic process that is used to deliver cytoplasmic material to the lysosome for degradation, and has been implicated in cancer and other disorders. Molecular alterations in the autophagy gene beclin1 are associated with human cancers, and studies in mice have shown that decreased beclin1 function causes dramatic increase in epithelial and hematopoietic malignancies. Beclin1 (Atg6 in flies) is a core component of the evolutionarily conserved Vps34/class III phosphatidylinositol 3 (PI3) kinase complex that regulates the formation of PI3 phosphate (PI3P) lipids. Although the Vps34 complex regulates autophagy, the function of PI3P in multiple vesicle compartments indicates that the tumor suppressor function of beclin1/Atg6 may be more complex than through the regulation of autophagy alone. Similar to beclin1 mutant mice, our data indicate that animals with null mutations in Drosophila beclin1 (Atg6) possess increased hematopoietic cells resulting in blood cell tumors. Significantly, Atg6 mutant clones of eye and ovarian follicle epithelial cells possess a growth advantage over wild- type cell neighbors that is not shared by cells with mutations in either Vps34 or the essential autophagy gene Atg1. These results indicate that significant differences exist between Atg6 and Vps34 mutant cells even though these genes are thought to encode core components of all PI3P regulatory complexes. Our data also suggest that the interpretation of beclin1 phenotypes likely over-simplify the function of this tumor suppressor. Therefore, our hypothesis is that Atg6 phenotypes are caused by alteration of more than autophagy alone. Our goal is to use the strength of Drosophila genetics to determine how Atg6 influences cell and tissue growth. Here we propose to: (1) determine Atg6 mutant cellular defects, (2) investigate the genetic relationship between Atg6, Ref(2)P/p62, NF-kB and tissue overgrowth, and (3) characterize novel factors and pathways that are involved in Atg6-regulated tissue overgrowth. The importance of Atg6/Beclin1 and the Vps34 regulatory complex in all normal cells and in cancer illustrate the significance of these studies.

Public Health Relevance

Autophagy is a conserved catabolic process that has been implicated in cancer. Molecular alterations in the autophagy gene beclin1/Atg6 are associated with human cancers. Although Beclin1/Atg6 regulates autophagy, the function of this tumor suppressor in multiple cellular processes indicates that the function of beclin1/Atg6 may be more complex than through the regulation of autophagy alone. Our results indicate that significant differences exist between beclin1/Atg6 and other regulators of autophagy. The importance of Beclin1/Atg6 in all normal cells, as well as in cancer, highlights the significance of these studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA159314-03
Application #
8449529
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Salnikow, Konstantin
Project Start
2011-06-16
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$320,858
Indirect Cost
$125,808
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Pérez, E; Das, G; Bergmann, A et al. (2015) Autophagy regulates tissue overgrowth in a context-dependent manner. Oncogene 34:3369-76
Mariño, Guillermo; Niso-Santano, Mireia; Baehrecke, Eric H et al. (2014) Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 15:81-94
Nelson, Charles; Baehrecke, Eric H (2014) Eaten to death. FEBS J 281:5411-7
Nelson, Charles; Baehrecke, Eric H (2014) Autophagy and cell death in the fly. Methods Enzymol 545:181-99
Tracy, Kirsten; Baehrecke, Eric H (2013) The role of autophagy in Drosophila metamorphosis. Curr Top Dev Biol 103:101-25
Shravage, Bhupendra V; Hill, Jahda H; Powers, Christine M et al. (2013) Atg6 is required for multiple vesicle trafficking pathways and hematopoiesis in Drosophila. Development 140:1321-9