Genetic Control of Programmed Cell Death in Drosophila. Programmed cell death (PCD) or apoptosis is a physiological process that is critical for normal development and tissue homeostasis. Defects in the regulation of PCD contribute to the pathogenesis of multiple diseases including those associated with reduced rates of cell death (cancer, autoimmunity) or with excessive cell death (neurodegeneration, stroke, myocardial infarction). The overall objective of our research is to gain a comprehensive understanding of the biological principles that underlie the regulation of PCD in the context of a multi-cellular organism, to identify and characterize the genes involved in this process, and to develop methods to manipulate them. Knowledge obtained in these studies will provide new insights into diseases that are associated with altered rates of apoptosis. We are using the genetic model organism Drosophila melanogaster for these studies. During Drosophila development many cells die by PCD. As in vertebrates, this cell death is not genetically predetermined in a lineage-restricted manner, but is dependent on environmental circumstances. Thus, Drosophila shares this developmental plasticity with vertebrates. Therefore, molecular genetic studies in Drosophila promise considerable potential for advancing our understanding of the basic control mechanisms involved in the regulation of apoptosis in vertebrates including humans. In the previous funding periods, we have performed genetic screens aimed at identifying genes involved in the control of PCD. We have identified approximately 30 genes which directly or indirectly regulate cell death. It is the overall goal to characterize these genes phenotypically and molecularly, and to reveal their function for the control of PCD. We have already revealed new biological principles by which cells control death and survival and will continue to do so in the future. Furthermore, these studies elucidate mechanisms by which potential tumor cells increase their resistance to apoptosis, a hallmark of cancer. Therefore, the characterization of these genes may have significant implications for the understanding of human diseases, and may help developing drugs and therapies to treat these diseases.

Public Health Relevance

This project investigates the genes and mechanisms that control Programmed Cell Death or Apoptosis. We have identified ~ 30 genes involved in the control of Programmed Cell Death which we wish to characterize. Examining these genes will elucidate new biological principles by which cells make death or survival decisions in the context of a multi-cellular organism and reveal mechanism by which tumor cells increase their survival, a hallmark of cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 1 Study Section (DEV1)
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Maas, Stefan
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University of Massachusetts Medical School Worcester
Schools of Medicine
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PĂ©rez, E; Das, G; Bergmann, A et al. (2015) Autophagy regulates tissue overgrowth in a context-dependent manner. Oncogene 34:3369-76
Fan, Yun; Bergmann, Andreas (2014) Multiple mechanisms modulate distinct cellular susceptibilities toward apoptosis in the developing Drosophila eye. Dev Cell 30:48-60
Huang, Q; Tang, X; Wang, G et al. (2014) Ubr3 E3 ligase regulates apoptosis by controlling the activity of DIAP1 in Drosophila. Cell Death Differ 21:1961-70
Fogarty, Caitlin E; Bergmann, Andreas (2014) Detecting caspase activity in Drosophila larval imaginal discs. Methods Mol Biol 1133:109-17
Christiansen, A E; Ding, T; Fan, Y et al. (2013) Non-cell autonomous control of apoptosis by ligand-independent Hedgehog signaling in Drosophila. Cell Death Differ 20:302-11
Woodfield, Sarah E; Graves, Hillary K; Hernandez, Jacob A et al. (2013) De-regulation of JNK and JAK/STAT signaling in ESCRT-II mutant tissues cooperatively contributes to neoplastic tumorigenesis. PLoS One 8:e56021
Anderson, Aimee E; Karandikar, Umesh C; Pepple, Kathryn L et al. (2011) The enhancer of trithorax and polycomb gene Caf1/p55 is essential for cell survival and patterning in Drosophila development. Development 138:1957-66
Lee, Tom V; Fan, Yun; Wang, Shiuan et al. (2011) Drosophila IAP1-mediated ubiquitylation controls activation of the initiator caspase DRONC independent of protein degradation. PLoS Genet 7:e1002261
Bergmann, A (2010) The role of ubiquitylation for the control of cell death in Drosophila. Cell Death Differ 17:61-7
Wang, Yuan; Chen, Zhihong; Bergmann, Andreas (2010) Regulation of EGFR and Notch signaling by distinct isoforms of D-cbl during Drosophila development. Dev Biol 342:1-10

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