In this study we will use the Drosophila eye to understand how metabolic stress caused by aberrant mitochondriaI function can affect proliferation. We have shown that mutations in nuclear genes that encode mitochondria! proteins show a block in the cell cycle. For one such mutation, tend, the cell cycle block is due to the activation of a specific pathway including AMPK and p53 leading to the down-regulation of Cyclin E. Although mutant cells show a remarkable reduction in intracellular ATP levels, they do not die, but differentiate and undergo normal morphogenesis. Preliminary data indicates that the mitochondrion affects the cell cycle in different ways, one through the downregulation of the cell cycle activator Cyclin E, while another through the upregulation of a cell cycle inhibitor Dacapo. In this proposal we intend to dissect the pathways that lead from the mitochondrion to the cell cycle. We will use genetic and cell culture studies to determine how Cyclin E is regulated in tend and Dacapo in pdsw. Additionally many more mutants showing a cell cycle defect were isolated in a genetic screen that we will further characterize to identify genes that link the mitochondrion with the cell cycle machinery. The phenomenon being investigated here is novel, and the Drosophila eye can provide important insights into normal mitochondrial function that is important for the well being of a eukaryotic cell. Furthermore, the work has long-term clinical relevance for tumor growth control and in the understanding of inherited diseases, including those of the eye, caused by mitochondrial dysfunction. ? ? ?

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
Zip Code
Wang, Cheng-Wei; Purkayastha, Arunima; Jones, Kevin T et al. (2016) In vivo genetic dissection of tumor growth and the Warburg effect. Elife 5:
Nagaraj, Raghavendra; Gururaja-Rao, Shubha; Jones, Kevin T et al. (2012) Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway. Genes Dev 26:2027-37
Mukherjee, T; Choi, I; Banerjee, Utpal (2012) Genetic analysis of fibroblast growth factor signaling in the Drosophila eye. G3 (Bethesda) 2:23-8
Rao, Shubha Gururaja; Banerjee, Utpal (2012) Oncogenic pathway utilizes mitochondrial fusion machinery to support growth. Cell Cycle 11:4491
Freije, William A; Mandal, Sudip; Banerjee, Utpal (2012) Expression profiling of attenuated mitochondrial function identifies retrograde signals in Drosophila. G3 (Bethesda) 2:843-51
Mandal, Sudip; Lindgren, Anne G; Srivastava, Anand S et al. (2011) Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells. Stem Cells 29:486-95
Yavari, Amir; Nagaraj, Raghavendra; Owusu-Ansah, Edward et al. (2010) Role of lipid metabolism in smoothened derepression in hedgehog signaling. Dev Cell 19:54-65
Mandal, Sudip; Freije, William A; Guptan, Preeta et al. (2010) Metabolic control of G1-S transition: cyclin E degradation by p53-induced activation of the ubiquitin-proteasome system. J Cell Biol 188:473-9
Evans, Cory J; Olson, John M; Ngo, Kathy T et al. (2009) G-TRACE: rapid Gal4-based cell lineage analysis in Drosophila. Nat Methods 6:603-5
Nagaraj, Raghavendra; Banerjee, Utpal (2009) Regulation of Notch and Wingless signalling by phyllopod, a transcriptional target of the EGFR pathway. EMBO J 28:337-46

Showing the most recent 10 out of 32 publications