The oncogene c-Myc is known to be involved in the development of many human cancers. Genomics and proteomics have identified many potential c-Myc targets involved in cell metabolism. Functional studies have shown that genes involved in glucose metabolism are regulated by c-Myc and our recent work provides evidence for Myc's involvement in oxidative phosphorylation (OXPHOS). However, the functional impact of Myc's regulation of metabolic genes has not been thoroughly investigated. Currently, the metabolic pathways essential for Myc-induced cancers are unknown and cannot be targeted for drug intervention. The first goal of this proposal is to generate metabolic profiles for Myc expressing cells under conditions where Myc induces growth, death or neoplasia in vivo and in vitro. The result generated from these studies will facilitate the identification of key points of intervention in metabolic pathways linked to Myc-induced neoplasia. A second goal is to identify Myc-induced genes involved in apoptosis and transformation. Knowing the identity of these genes will enable future studies to develop methods that induce apoptosis or disable transformation in Myc expressing cancer cells.
The specific aims of this proposal include: 1) to determine how Myc's ability to control glucose metabolism and OXPHOS influences the flow of carbon metabolites through glycolysis and the TCA cycle under conditions that are conducive to growth, death or neoplasia and 2) to identify and characterize genes that are involved in Myc-induced apoptosis and transformation. The studies in this proposal utilize tissue specific, inducible transgenic mouse and cell models to understand the changes in energy metabolism that occur on up-regulation of c-Myc. These studies will involve an analysis of carbon flow and metabolic flux using 13C NMR and isotopomer analysis. Mitochondrial metabolism will be evaluated by oxygen consumption, OXPHOS enzyme assays, membrane potential and reactive oxygen species generation. Carbon metabolism is essential to cell survival and proliferation and we would expect that our metabolic approach would provide a greater understanding of the metabolic events underlying c-Myc induced neoplastic transformation and thereby provide novel target for cancer therapeutics. ? ?
| Morrish, Fionnuala; Noonan, Jhoanna; Perez-Olsen, Carissa et al. (2010) Myc-dependent mitochondrial generation of acetyl-CoA contributes to fatty acid biosynthesis and histone acetylation during cell cycle entry. J Biol Chem 285:36267-74 |
| Ahuja, Preeti; Zhao, Peng; Angelis, Ekaterini et al. (2010) Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice. J Clin Invest 120:1494-505 |
| Morrish, Fionnuala (2009) micRo-manageMeNT of MYC during hypoxia. Cell Cycle 8:2865 |
| Morrish, F; Isern, N; Sadilek, M et al. (2009) c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry. Oncogene 28:2485-91 |
| Morrish, Fionnuala; Neretti, Nicola; Sedivy, John M et al. (2008) The oncogene c-Myc coordinates regulation of metabolic networks to enable rapid cell cycle entry. Cell Cycle 7:1054-66 |
