MYC, Metabolism and Cancer Molecular genetics lab Eungyoung Kim
Outline Hallmarks of cancer MYC protein MYC function Building a cell Nutrient sensing Intermediary metabolism and macromolecular synthesis Organelle biogenesis Cell cycle progression Cancer therapy and Outlook 미국자료- http://onlinelibrary.wiley.com/doi/10.3322/caac.21254/pdf
MYC protein Hallmarks of cancer
MYC protein Hallmarks of cancer
MYC MYC protein Hallmarks of cancer - c-Myc, N-Myc, L-Myc - transcription factor that dimerizes with MAX to bind DNA and regulate gene expression nuclear localization sequence, DNA-binding domain, helix–loop–helix dimerization domain, and transcriptional regulatory domain underlie this functional ability.
MYC protein Hallmarks of cancer MYC enhances transcription and translation
MYC protein Hallmarks of cancer Growth factor dependent MYC activity Growth factor independent MYC activity
MYC protein Hallmarks of cancer MYC regulation in noncancerous and cancerous cells
MYC function Hallmarks of cancer 1. Building a cell Maintenance of cell membrane potentials, homeostasis for redox control and protein synthesis, are major energy-demanding cellular processes that must be sustained for survival. in the case of resting memory T cells 1) a major source of energy for homeostasis is a futile cycle of oxidation of de novo–synthesized lipids 2) MYC-mediated proliferating cells use de novo lipogenesis to produce membranes for cell growth ; Glucose and glutamine carbons are imported into cells and converted to citrate for lipogenesis ; resting T cells oxidize the de novo–.synthesized fatty acids for ATP production. Once stimulated, T cells begin to acquire nutrients, particularly glucose and glutamine, and convert them to the necessary components for making new DNA and RNA, new enzymes, new cytoskeleton, new membranes, new organelles, and new copies of genetic material
2. Nutrient sensing, FOXO, HIF, and MYC MYC function Hallmarks of cancer 2. Nutrient sensing, FOXO, HIF, and MYC - lower organisms have developed nutrient-sensing mechanisms that are coordinated with growth. Nutrient insufficiency causes decreased TORC signaling, resulting in the inhibition of the production of ribosomes and cell growth through the activation of DOT6 and TOD6 In mammalian cells; With severe starvation or pathologic processes that disrupt tissue perfusion, cell-autonomous nutrient-sensing mechanisms protect cells through pathways aimed at preserving adequate ATP pools. - The mTOR, AMP kinase (AMPK), and GCN2 pathways are key to survival of cells under nutrient deprivation. Lack of amino acids attenuates mTOR activity through sensing by the RAG proteins on the lysosomal membrane
2. Nutrient sensing, FOXO, HIF, and MYC MYC function Hallmarks of cancer 2. Nutrient sensing, FOXO, HIF, and MYC Mammalian MYC activity also depends on nutrient status sensed through mTOR via mTOR’s regulation of MYC translation nutrient sufficiency and growth factor signaling are required for MYC to carry out its transcriptional program With nutrient starvation, diminished TOR activity attenuates cell growth through diminished expression of dMyc. This pathway appears to involve TOR-dependent AKT phosphorylation
2. Nutrient sensing, FOXO, HIF, and MYC MYC function Hallmarks of cancer 2. Nutrient sensing, FOXO, HIF, and MYC With nutrient starvation, diminished TOR activity attenuates cell growth through diminished expression of dMyc. This pathway appears to involve TOR-dependent AKT phosphorylation
MYC function Hallmarks of cancer 3. Intermediary metabolism and macromolecular synthesis
MYC function Hallmarks of cancer 4. Organelle biogenesis Ribosome
Mitochondria Other organelles MYC function Hallmarks of cancer 4. Organelle biogenesis Mitochondria Other organelles
MYC function Hallmarks of cancer 5. Cell cycle progression
MYC function Hallmarks of cancer 5. Cell cycle progression
cancer therapy involved the use of anti-folates LDHA inhibitor Cancer therapy and Outlook Hallmarks of cancer cancer therapy involved the use of anti-folates LDHA inhibitor GLS inhibitor lactate exporter MCT1 inhibitor NAMPT inhibitor …. → combination therapy would be the most promising metabolic inhibition strategy in the clinic
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