Vuree 2017 MiP2017
- G0/G1 transition is critical in transformation of cells.
- Tumour mass increases when tumour initiating cells (CSC) proliferate
- They need to activate mitochondrial respiratory and energy metabolism for proliferation
- Metabolic reprogramming in proliferative cells is active only in G1 phase of cell cycle
- We hypothesize that five transcription factors (TFs), p53, c-Myc, HIF1 and HIF 2, and FoxO, modulate the metabolism during G1 phase.
- This interaction generates acetyl CoA in three phases; i) p53 mediated oxidation of fatty acids, independent of TCA cycle ii) Myc mediated oxidation of leucine in mitochondrial matrix and iii) citrate hydrolysis by ATP citrate lyase (ACL) in the cytoplasm.
The present study used the system biology approaches to understand the saptio-temporal relations in activation/ deactivation of tumour metabolism, epigenetics and cell survival pathways. Spatio-Temporal and Protein-Protein Interaction (Gene networking) analysis was done using datasets and tools like Genemania, Cytoscape, and String database was used for analysis of functional protein interactions Transcriptional Factors (TFs), p53, c-MYC, HiF1, EPAS1(hif2a), FOXO1 and trans acetylases, p300, CREBBP, and GCN5. Individual interactions between each TFs and transacetylases were also cross checked and significant interactions relevant to metabolic and gene reprogramming observed are accorded. p53, mediated fatty acid oxidation, and Myc mediated oxidation of leucine oxidation generate acetyl CoA, in mitochondria. While ATP citrate lyase generates acetyl CoA from citrate in cytoplasm. They differentially activate the trans acetylases at different time points. We examined the relation of transcription factors, acetyl CoA and three key trans acetylases, CBP binding protein, p300, and GCN5, and find temporal, spatial differentiation in activation of genes related to inflammation, nutrient transport, amino acid sensors, and biosynthetic programs activated by ATF proteins, FoxO and PI3K- Akt -mTOR pathways, which are involved in cell survival, proliferation and differentiation.
• Bioblast editor: Kandolf G
Labels: Pathology: Cancer
- Vuree S(1), Suravajhala P(2), Rao RK(1), Raghunath M(1), Sinha S(3), Digumarthi R(4), Vishnupriya S(5), Lakshmipathi V(6)
- National Inst Nutrition/ NAR-BR (NCLAS) (ICMR), Hyderabad, Telangana
- Dept Biotechnol Bioinformatics, Birla Inst Scientific Research, Jaipur
- MNJ Inst Oncology Regional Cancer Centre, Hyderabad, Telangana
- Homi Bhabha Cancer Hospital Research Centre, Visakhapatnam, AP
- Dept Genetics, Osmania Univ, Hyderabad, Telangana
- Dept Zoology, Kakatiya Univ, Warangal, Telangana. - [email protected]