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Regulation of metabolism by the oncoprotein c-Myc

Edmunds, Lia (2015) Regulation of metabolism by the oncoprotein c-Myc. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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c-Myc (hereafter Myc), a transcription factor that regulates a variety of cellular functions including growth and differentiation, is deregulated in many different types of cancers. Myc regulates the Warburg effect and oncogenic biosynthesis, but also many aspects of metabolism, believed to be a pivotal point of transformation. Myc is known to control glycolysis and glutaminolysis but little is known about the interplay between glucose, amino acid, and fatty acid oxidation. We hypothesize Myc integrates glucose, amino acid, and fatty acid utilization for energy, and either loss- or gain-of-function will disrupt metabolic homeostasis.
Loss of Myc in rat fibroblasts elicits a severe energy deficit, including diminished acetyl-coA levels, to which they respond by enhancing FAO and lipid uptake and storage. Using an in vivo model, we found murine hepatocytes respond to Myc ablation with a milder phenotype. They display metabolic defects, including reduced respiratory chain capacity and an increased metabolic rate when fed a high-fat diet. Additionally, hepatocytes had major lipid defects including transcriptional deregulation, lipid accumulation and increased FAO.
Reduced ATP in Myc KO fibroblasts constitutively activates AMPK, a protein which limits anabolism for catabolism, leading us to hypothesize AMPK may play a role in Myc deregulated phenotypes. We found AMPK controls mitochondrial structure and function in conjunction with Myc over-expression, via redox state, electron transport chain (ETC) capacity, and TCA cycle dehydrogenases. Additionally, AMPK KO cells demonstrate transcriptional and translational differences and differential responses in regulating glycolysis, which results in
Lia Rae Edmunds, Ph.D.
University of Pittsburgh, 2015
metabolite dysfunction, when exposed to Myc over-expression. Thus, AMPK is critical to supporting metabolic pathways in response to Myc deregulation.
To ascertain if Myc plays a role in hepatic proliferative capacity, we turned to a mouse model of hereditary tyrosinemia. We definitively proved that Myc is not required for prolonged hepatocyte proliferation, even in direct competition with Myc-replete hepatocytes. Proliferating KO hepatocytes were associated with a pro-inflammatory environment that correlated with worsening lipid accumulation and lipid oxidation-mediated liver damage, a phenotype reminiscent of non-alcoholic fatty liver-like disease. Throughout this work, we reveal Myc-regulated metabolism is vital for maintaining lipid homeostasis and energy production, but dispensable for sustained hepatic proliferation.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Edmunds, Lialre13@pitt.eduLRE130000-0002-9667-0249
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairProchownik, Edward V.evp4@pitt.eduEVP4
Committee MemberGoetzman, Eric S.esg5@pitt.eduESG5
Committee MemberO'Doherty, Robert Mrmo1@pitt.eduRMO1
Committee MemberVan Houten, Bennettvanhoutenb@upmc.eduBEV15
Date: 10 December 2015
Date Type: Publication
Defense Date: 16 November 2015
Approval Date: 10 December 2015
Submission Date: 9 December 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 192
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biochemistry and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Mitochondria, Electron Transport Chain (ETC), Non-alcoholic fatty liver disease (NAFLD), fatty acid b-oxidation, AMP-activated protein kinase (AMPK), Warburg effect
Date Deposited: 10 Dec 2015 13:24
Last Modified: 19 Dec 2016 14:43


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