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Homeostatic control of IkappaB metabolism determines NF- kappaB responsiveness

  • Author(s): O'Dea, Ellen Louise
  • et al.
Abstract

Cellular signal transduction begins with an input signal that activates a pathway or network of signaling proteins to exert a specific output or change in cellular behavior. A useful approach to understanding signal transduction and mapping signaling pathways has been to examine changes to specific proteins, either in their expression, interaction with other proteins, post-translation modifications, or enzymatic activities, in cells after application of the input. As useful as this approach may be, it does not answer how the pathway may be regulated in the absence of an input signal, nor does it explain how the output may be more or less responsive to an input depending on the homeostatic regulation within the particular network. Tight regulation of the NF-[kappa]B transcription factor is mediated by the coordinated control of the synthesis and degradation of the inhibitor of NF-[kappa]B proteins, the I[kappa]Bs. My dissertation takes a mechanistic approach to understanding how steady state I[kappa]B synthesis and degradation affect constitutive NF-[kappa]B activity and NF-[kappa]B responses to inflammatory and metabolic stress signals. Biochemistry, genetics, and molecular biology, are used in conjunction with mathematical modeling to explore how homeostatic mechanisms determine UV-induced NF-[kappa]B activity and how type I and type II interferons alter NF-[kappa]B responsiveness to inflammatory signals. This work suggests that the targeting of the steady-state reactions of a network may be important consideration when designing therapeutics to specifically target certain aspects of a signaling pathway

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