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Download networks to increase mitochondrial function, cell cycle entry and
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Oncogene integration of “omic” networks to increase mitochondrial function, cell cycle entry and tumor progression. Fionnuala Morrish, Ph.D. Clinical Division Fred Hutchinson Cancer Research Center Outline of talk Interconnection of –omic networks The oncogene c-Myc Regulation of mitochondrial function and cell metabolism during cell cycle entry Regulation of substrate supply for protein acetylation Regulation of metabolism during tumor progression and regression Interconnected –omic networks Transcriptome Metabolome Proteome Metabolite modified Proteome Palmitoylation Acetylation O-GlcNAcylation Farnsylation The oncogene c-Myc Transcription factor regulating 15% of genome Chromatin remodelling Embryonic stem cell re-programming Cell cycle regulator Pervasive oncogene Endogenous Myc required for tumor maintenance Myc regulation of mitochondrial function and cell metabolism during serum induced cell cycle entry c-myc +/+ 0hr c-myc-/16hr 0hr 16hr Mitochondrial genes targets induced by Myc on cell cycle entry Morrish et al. Genes and Development 2003 Network of genes regulated by Myc Myc bioenergetic phenotype Oxygen consumption and extracellular acidification rate Myc+/+ Myc-/-MycER Myc-/Myc-/-E1A Bioenergetic cell cycle checkpoints Experimental design for analysis of metabolism during cell cycle entry Myc-/- Myc+/+ Myc-/-MycER Quiescent Plate in 10% serum Oxygen Glucose Lactate Cell cycle analysis ATP Pyruvate Mitochondrial mass And potential Temporal regulation of cellular bioenergetics Serum addition Cell cycle entry Quiescent 3 hr 3 hr 8 hrs 16 hrs 8 hr 16 hr 3 hr 8 hrs 16 hrs Morrish et al. Cell Cycle 2008 Mitochondrial function is required during Myc induced cell cycle entry 2-DG Rotenone Oligomycin Myc regulates metabolic cell cycle checkpoints in response to serum Mitochondrial biogenesis and function Increased Increased Increased Increased membrane potential mitochondrial mass oxygen consumption ATP Glycolysis Increased lactate production Increased glucose uptake Myc regulation of substrate supply for protein acetylation Myc regulation of gene transcription in interconnected metabolic networks Morrish et al. Cell Cycle 2008 Myc regulated flux increases acetyl CoA production from mitochondria Myc regulation of histone acetylation [U-13C] Glucose [U-13C]-Pyruvate 13C-FA, 13C-acetate and 13C-acetoacetate [U-13C]-Acetyl-CoA TCA cycle GCN5 [U-13C]-Citrate 13C-Ac Nuclear histones 13C-Ac
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