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Insights into the homeostatic regulation of I kappa B alpha

Abstract

The regulation of the transcription factor NF-\[kappa\]B is crucial to proper cell physiology, as misregulation of this transcription factor can lead to many disease states, including chronic inflammation and cancer. NF-\[kappa\]B is inhibited by a class of inhibitor proteins known as I kappa B; the most effective I\[kappa\]B is I\[kappa\]B\[alpha\]. Signal induced degradation of I\[kappa\]B\[alpha\] leading to NF-\[kappa\]B translocation and activation is well documented and requires post-translational modifications such as phosphorylation and ubiquitination. It has recently been demonstrated that I\[kappa\]B alpha also undergoes stimulus-independent degradation and this degradation pathway might be important for NF-\[kappa\]B activity regulation. The focus of this study is to investigate the mechanism of stimulus independent degradation of I\[kappa\]B alpha and its effect on NF- \[kappa\]B activity. Chapter 1 introduces the NF-\[kappa\]B: I\[kappa\]B signaling system, ubiquitin-independent degradation of several substrates, and also various regulatory proteasome complexes. Chapter 3 describes the delineation of the pathways regulating the degradation of I\[kappa\]B\[alpha\]. Results presented here show that the degradation pathway of I\[kappa\]B alpha is determined by binding to NF-\[kappa\]B subunits. It is further shown that perturbations of ubiquitin-independent degradation pathway alter NF-\[kappa\]B activation. Chapter 4 focuses on the ankyrin repeat sequence of I\[kappa\]B alpha. Of the six ankyrin repeats present in I\[kappa\]B alpha, several deviate from the consensus ankyrin repeat sequence. Mutations back to the consensus sequence in several ankyrin repeats demonstrate that the location of thermodynamic stabilization determines the degradation rate of I\[kappa\]B\[alpha\]. Finally, Chapter 5 dissects the degradation requirements of I\[kappa\]B alpha. Our results show that there are two degrons within I\[kappa\]B\[alpha\]; one located in the 5th ankyrin repeat, and the other within the PEST domain of I\[kappa\]B\[alpha\]. Both degrons are controlled by hydrophobic residues within long stretches of flexible regions.

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