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Fionnuala Morrish, Ph.D. Clinical Division Fred Hutchinson Cancer Research Center

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

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Fionnuala Morrish, Ph.D. Clinical Division Fred Hutchinson Cancer Research Center

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  1. 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

  2. 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

  3. Interconnected –omic networks Transcriptome Metabolome Proteome Metabolite modified Proteome Palmitoylation Acetylation O-GlcNAcylation Farnsylation

  4. 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

  5. Myc regulation of mitochondrial function and cell metabolism during serum induced cell cycle entry c-myc +/+ c-myc-/- 0hr 16hr 0hr 16hr Landay et al 2000

  6. Mitochondrial genes targets induced by Myc on cell cycle entry Morrish et al. Genes and Development 2003

  7. Network of genes regulated by Myc

  8. Myc bioenergetic phenotype Oxygen consumption and extracellular acidification rate Myc+/+ Myc-/-MycER Myc-/- Myc-/-E1A

  9. Bioenergetic cell cycle checkpoints

  10. 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 Mitochondrial mass And potential Pyruvate ATP

  11. Temporal regulation of cellular bioenergetics Serum addition Cell cycle entry Quiescent 3 hr 8 hr 16 hr 3 hr 8 hrs 16 hrs 3 hr 8 hrs 16 hrs Morrish et al. Cell Cycle 2008

  12. Mitochondrial function is required during Myc induced cell cycle entry Rotenone 2-DG Oligomycin

  13. Myc regulates metabolic cell cycle checkpoints in response to serum • Mitochondrial biogenesis and function • Increased membrane potential • Increased mitochondrial mass • Increased oxygen consumption • Increased ATP • Glycolysis • Increased lactate production • Increased glucose uptake

  14. Myc regulation of substrate supply for protein acetylation

  15. Myc regulation of gene transcription in interconnected metabolic networks Morrish et al. Cell Cycle 2008

  16. Myc regulated flux increases acetyl CoA production from mitochondria

  17. Myc regulation of histone acetylation [U-13C] Glucose [U-13C]-Pyruvate 13C-FA, 13C-acetate and 13C-acetoacetate TCA cycle [U-13C]-Acetyl-CoA GCN5 [U-13C]-Citrate 13C-Ac 13C-Ac Nuclear histones

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