Exploring the Metabolic Regulation of p53 from Ribosomal Proteins to Very Long Chain Fatty Acids Public Deposited

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  • March 20, 2019
Creator
  • Franklin, Derek
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • The tumor suppressor p53 is the most well-studied gene in biology. The majority of studies have focused on the ability of p53 to control cell cycle arrest, cellular senescence, and apoptosis. Surprisingly, recent studies in mice that retain p53-mediated metabolic regulation and DNA damage repair but lack these three canonical functions exhibit significant tumor suppression. However, the effects of nutrient availability on p53 and p53-mediated metabolic regulation require additional study. Importantly, we have previously shown that ribosomal proteins bind to MDM2, the primary negative regulator of p53, stabilizing p53 in response to stress. Studies of mice deficient in ribosomal protein-Mdm2 binding demonstrated that p53 regulates lipid catabolism in the liver during starvation. These ribosomal protein-Mdm2 binding-deficient mice were then evaluated in response to high fat diet feeding. p53 was similarly activated in a ribosomal protein dependent manner, but surprisingly p53 activation promoted energy storage in the adipose tissue through altered regulation of Glut4 and Sirt1. Therefore, p53 responds to various levels of nutrient availability to regulate lipid metabolism in multiple tissues. In my dissertation work, I mined a previously published mRNA microarray in order to determine potential mechanisms for the metabolic phenotypes that were observed in the previous mouse studies. From this work, I identified two novel p53 target genes associated with metabolism. Interestingly, the peroxisomal gene carnitine O-octanoyl transferase (CROT) was identified and is known to regulate very long chain fatty acid (VLCFA) metabolism. Further study completed by me established CROT as a novel p53 target gene in multiple human cancer cell lines. I completed additional experiments that suggest that CROT expression affects cellular signaling by modulating lipid raft formation through VLCFA-containing sphingolipids. A rate limiting enzyme in glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), was also identified from this p53 microarray, and further studies using mouse embryonic fibroblast cells along with human cancer cell lines demonstrated that p53 regulates glucose metabolism to facilitate nucleotide production in response to DNA damage. In summary, I have identified two novel p53 target genes by which p53 regulates cellular metabolism to affect multiple tumor suppressive functions.
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  • In Copyright
Advisor
  • Cox, Adrienne
  • Emanuele, Michael
  • Graves, Lee
  • MacDonald, Jeffrey
  • Zhang, Yanping
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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