Cell/cell communication controls many aspects of cellular physiology including cell proliferation, cell differentiation and cell death/survival. However, the complexity of multi-cellular organisms has made it difficult to obtain a comprehensive understanding of all extracellular signaling mechanisms controlling these aspects. This research project focuses on the control of cell survival by extracellular, or non-autonomous, signaling. We have identified mutants in tumor-suppressor-like genes that control the secretion of extra-cellular factors which promote the survival of neighboring cells. These studies reveal interactions between cells which are very relevant for tissue homeostasis, and abnormalities may be directly linked to the parthenogenesis of human diseases including cancer. For example, animals containing mutant clones of these tumor suppressor-like genes are characterized by tissue overgrowth and tumor-like masses. In some of these mutants, Notch activity is inappropriately activated which stimulates proliferation and survival in a non-autonomous manner. Inappropriate Notch activation has been implicated for the genesis of many human cancers. Our data demonstrate that cell proliferation is not sufficient for generation of the tumor masses;instead increased cell survival is necessary for full development of tumors. Therefore, an understanding of the genetic and molecular mechanisms that control non-autonomous cell survival is crucial for the prevention and treatment of these diseases. It is the main goal of this proposal to further our understanding about the mechanisms that regulate non-autonomous survival. For this purpose, we are using the highly accessible genetic model organism Drosophila melanogaster.
Our specific aims are: 1. Identify the genes in the signal-sending cell that control non-autonomous cell survival. 2. Identify the mechanisms which lead to secretion of signaling molecules that control cell survival in neighboring cells. 3. Identify the signals and the mechanisms in the signal-receiving cell that control non-autonomous survival. This project will be the first systematic approach to identify all genes and mechanisms that control non- autonomous survival in any organism. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM081543-04
Application #
7866581
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Zatz, Marion M
Project Start
2007-09-01
Project End
2011-08-31
Budget Start
2010-07-01
Budget End
2011-08-31
Support Year
4
Fiscal Year
2010
Total Cost
$283,443
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Anderson, Aimée 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
Fan, Y; Bergmann, A (2010) The cleaved-Caspase-3 antibody is a marker of Caspase-9-like DRONC activity in Drosophila. Cell Death Differ 17:534-9
Fan, Y; Lee, T V; Xu, D et al. (2010) Dual roles of Drosophila p53 in cell death and cell differentiation. Cell Death Differ 17:912-21
Herz, Hans-Martin; Madden, Laurence D; Chen, Zhihong et al. (2010) The H3K27me3 demethylase dUTX is a suppressor of Notch- and Rb-dependent tumors in Drosophila. Mol Cell Biol 30:2485-97
Bergmann, Andreas; Steller, Hermann (2010) Apoptosis, stem cells, and tissue regeneration. Sci Signal 3:re8
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
Herz, Hans-Martin; Bergmann, Andreas (2009) Genetic analysis of ESCRT function in Drosophila: a tumour model for human Tsg101. Biochem Soc Trans 37:204-7
Herz, Hans-Martin; Woodfield, Sarah E; Chen, Zhihong et al. (2009) Common and distinct genetic properties of ESCRT-II components in Drosophila. PLoS One 4:e4165

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