Probing the complexity of UV induced apoptosis in Drosophila: Apoptosis is an evolutionarily conserved process that has been implicated in a variety of diseases, including cancer and neurodegenerative diseases. Regulation of apoptosis is under the control of a complex network of genes (proteins). Our preliminary data showed that UV induced apoptosis in Drosophila embryo can be mediated by different cell death regulatory genes. More interestingly, the cellular context (differentiation status) of the irradiated cell determines which cell death regulatory gene is activated to induce cell death upon UV irradiation, i.e. When embryos in differentiating stage were irradiated with UV, the reaper gene is induced by a DNA damage -dependent mechanism that involves Drosophila homologue of Ataxia Telangiectasia Mutated, mei-41 (and very likely dP53 as well). However, when embryos prior to differentiating stage were irradiated, the hac-1 (Homologue of Apaf-1 and Ced-4) gene is induced instead of reaper. The induction of hac-1 expression is required for UV induced apoptosis at this developmental stage. But in contrast to UV induction of reaper, UV induction of hac-1 appears to be independent of nuclear DNA damage and was not affected by mei-41 mutation (mei-41 [D5]). It has long been noticed that UV induced cell death can be mediated by DNA damage -dependent and -independent mechanisms. However, it remains unclear as to how are the mechanisms deployed and coordinated to mediate UV induced apoptosis. The aforementioned findings indicate that Drosophila embryo provides an excellent model for systematic analysis of the complexity of UV -induced cell death. The focus of this proposal is to characterize the molecular mechanism underlying UV induced hac- 1 expression and apoptosis in early stage embryos. In addition, we will apply genomic approaches to gain comprehensive understanding of UV -induced genomic response and apoptosis. The goal of this proposal is to elucidate in depth how different cell death regulatory pathways may be deployed to mediate genotoxic stimuli -induced cell death. The information provided by these investigations will contribute to our comprehensive understanding of cell death regulation and skin carcinogenesis. Molecular mechanisms uncovered through this project should provide insights for identifying alternative therapeutic targets, especially for cancers that are resistant to DNA-damage agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA095542-01A2
Application #
6687517
Study Section
Special Emphasis Panel (ZRG1-CDF-5 (90))
Program Officer
Pelroy, Richard
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$275,579
Indirect Cost
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Zhang, C; Casas-Tintó, S; Li, G et al. (2015) An intergenic regulatory region mediates Drosophila Myc-induced apoptosis and blocks tissue hyperplasia. Oncogene 34:2385-97
Zhang, Can; Liu, Bo; Li, Guangyao et al. (2011) Extra sex combs, chromatin, and cancer: exploring epigenetic regulation and tumorigenesis in Drosophila. J Genet Genomics 38:453-60
Lin, Nianwei; Li, Xingguo; Cui, Kairong et al. (2011) A barrier-only boundary element delimits the formation of facultative heterochromatin in Drosophila melanogaster and vertebrates. Mol Cell Biol 31:2729-41
Lin, Nianwei; Zhang, Can; Pang, John et al. (2009) By design or by chance: cell death during Drosophila embryogenesis. Apoptosis 14:935-42
Bryant, B; Zhang, Y; Zhang, C et al. (2009) A lepidopteran orthologue of reaper reveals functional conservation and evolution of IAP antagonists. Insect Mol Biol 18:341-51
Zhang, Yanping; Lin, Nianwei; Carroll, Pamela M et al. (2008) Epigenetic blocking of an enhancer region controls irradiation-induced proapoptotic gene expression in Drosophila embryos. Dev Cell 14:481-93
Bennett, Richard L; Blalock, William L; Choi, Eun-Jung et al. (2008) RAX is required for fly neuronal development and mouse embryogenesis. Mech Dev 125:777-85
Meng, Hailong; Banerjee, Arunava; Zhou, Lei (2007) BLISS 2.0: a web-based tool for predicting conserved regulatory modules in distantly-related orthologous sequences. Bioinformatics 23:3249-50
Meng, Hailong; Banerjee, Arunava; Zhou, Lei (2006) BLISS: binding site level identification of shared signal-modules in DNA regulatory sequences. BMC Bioinformatics 7:287
Zhou, Lei; Jiang, Guohua; Chan, Gina et al. (2005) Michelob_x is the missing inhibitor of apoptosis protein antagonist in mosquito genomes. EMBO Rep 6:769-74

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