The long term objective of this research is to elucidate the molecular mechanisms by which cell proliferation or differentiation is controlled in animal development. Specifically, the research in this grant will use the Drosophila developing retina as a model system to investigate the mechanisms by which developmental signaling pathways such as Notch and cell intrinsic transcription factors such as atonal and daughterless interact to control cell proliferation and differentiation. Atonal is a bHLH family of transcription factor that is required for the initiation of photoreceptor cell differentiation. The induction of atonal in the developing eye requires Notch signaling, a conserved developmental pathway that has diverse roles in normal development. Notch signaling has also been implicated in regulating the cell cycle, however activation of Notch signaling will induce cell proliferation in some cell types while induce cell cycle arrest and differentiation in others. The mechanisms by which Notch signaling leads to cell proliferation or cell cycle arrest in distinct cell types remains elusive. The Drosophila developing retina provides a unique developmental system that is ideally suited for this investigation because of the well-characterize patterns of cell proliferation and the developmental signaling and because of the ease of generating loss or gain of function cell clones that can be precisely identified during development. Furthermore, the eye-specific enhancers for three of Notch's cell proliferation and differentiation targets have been identified. In this grant, we use these reagents to investigate the mechanism by which Notch signaling regulates cell proliferation in the Drosophila developing retina. Specifically, we propose to (1) determine the role of Notch signaling in cell cycle regulation and in the regulation of cyclin E and Dacapo; (2) determine the role of atonal and daughterless in coordinating cell cycle arrest with cell differentiation; and (3) determine the mechanism by which Notch and other developmental signaling pathways regulate atonal expression and cell proliferation or differentiation. Since the Notch pathway is conserved in mammalian systems and is often deregulated in human diseases including cancers, the proposed studies will provide significant new insight into the roles of Notch signaling in developmentally regulated cell proliferation as well as in human cancers. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM074197-01A1S1
Application #
7178326
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Haynes, Susan R
Project Start
2006-02-01
Project End
2010-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$55,854
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Zhang, Tianyi; Sheng, Zhentao; Du, Wei (2016) Loss of histone deacetylase HDAC1 induces cell death in Drosophila epithelial cells through JNK and Hippo signaling. Mech Dev 141:4-13
Sheng, Zhentao; Yu, Lijia; Zhang, Tianyi et al. (2016) ESCRT-0 complex modulates Rbf-mutant cell survival by regulating Rhomboid endosomal trafficking and EGFR signaling. J Cell Sci 129:2075-84
Zhang, Zhiyu; Li, Zejuan; Wu, Xiaohui et al. (2015) TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol. J Pharmacol Sci 127:83-91
Zhang, Tianyi; Du, Wei (2015) Groucho restricts rhomboid expression and couples EGFR activation with R8 selection during Drosophila photoreceptor differentiation. Dev Biol 407:246-55
Tanaka-Matakatsu, Miho; Miller, John; Du, Wei (2015) The homeodomain of Eyeless regulates cell growth and antagonizes the paired domain-dependent retinal differentiation function. Protein Cell 6:68-78
Jin, H R; Liao, Y; Li, X et al. (2014) Anticancer compound Oplopantriol A kills cancer cells through inducing ER stress and BH3 proteins Bim and Noxa. Cell Death Dis 5:e1190
Tanaka-Matakatsu, Miho; Miller, John; Borger, Daniel et al. (2014) Daughterless homodimer synergizes with Eyeless to induce Atonal expression and retinal neuron differentiation. Dev Biol 392:256-65
Zhao, Jiong; Zhang, Zhenyu; Liao, Yang et al. (2014) Mutation of the retinoblastoma tumor suppressor gene sensitizes cancers to mitotic inhibitor induced cell death. Am J Cancer Res 4:42-52
Zhang, Tianyi; Liao, Yang; Hsu, Fu-Ning et al. (2014) Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities. PLoS Genet 10:e1004357
Wang, Chong-Zhi; Li, Binghui; Wen, Xiao-Dong et al. (2013) Paraptosis and NF-?B activation are associated with protopanaxadiol-induced cancer chemoprevention. BMC Complement Altern Med 13:2

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