Examining novel roles for the IκB kinase in coordinating the cellular response to metabolic stress Public Deposited

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  • March 20, 2019
Creator
  • Comb, William C.
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • The induction of mammalian autophagy, a conserved cellular bulk-degradation process, was recently shown to require Inhibitor of κB (IκB) Kinase (IKK), the upstream regulator of nuclear factor (NF)-κB transcription factors. In response to cell stress IKK has been exclusively studied for its ability to activate NF-κB-dependent pro-inflammatory gene expression; surprisingly this activity is not required for starvation-induced autophagy and the mechanism by which IKK promotes this activity are largely unknown. Here we investigate the role of IKK/NF-κB pathway in response to both acute and prolonged nutrient deprivation, a classic autophagy- and novel NF-κB-inducing stimulus. We demonstrate that classic IKK-dependent NF-κB activation and gene expression occurs in response to cell starvation. Independently, IKK controls expression of genes necessary for autophagic machinery in response to prolonged starvation. The work presented in Chapter 2 will demonstrate that IKK is important molecule upstream of changes in gene expression induced by cellular starvation. IKK activity in response to acute starvation is also explored within and we identify that this kinase is important for transducing signals that inhibit growth and metabolic pathways. We find that IKK is required for inhibition of growth factor-dependent signaling through phosphorylation of the novel IKK substrate Phosphoinonsitide 3-Kinase (PI3K). The work outlined in Chapter 3 identifies a novel cross-talk mechanism between growth and stress responsive signal transduction pathways important for coordinating the cellular response to nutrient availability. In summary, the following manuscript will identify two novel functions for the IKK complex in regulating nutrient sensitive pathways, establishing the critical role of this kinase in cellular adaptation to metabolic stress.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Genetics & Molecular Biology"
Advisor
  • Baldwin, Albert
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  • Chapel Hill, NC
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  • Open access
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