UC San Diego

The NF[kappa]B signaling network mediates numerous physiological functions such as growth and development, inflammatory responses, immune responses, and is implicated in several human diseases. While stimulus- responsive NF[kappa]B activity mediated by the inhibitor of NF[kappa]B (I[kappa]B) degradation and feedback re- synthesis is mechanistically well understood, little is known about the mechanisms that control the formation of specific NF[kappa]B dimers. Indeed, different cell types have distinct repertoires of NF[kappa]B dimers, so studying the mechanisms that control specific NF[kappa]B dimer generation is critical for understanding the cell- type-specific functions of the NF[kappa]B signaling system. Two NF[kappa]B signaling pathways have been described: the canonical pathway that mediates transient inflammatory responses and the non-canonical pathway that mediates sustained developmental signaling. However, because there are numerous physical and functional interconnections, we consider here the two pathways as being mediated by a single signaling system. While regulatory interdependence has been described, the effectors of the two pathways do have distinct biological functions. An understanding of regulatory crosstalk within the NF[kappa]B signaling system is crucial for characterizing the specificity of cellular responses in various physiological states and their biological relationship. My dissertation aims to understand the molecular mechanisms controlling NF[kappa]B dimer generation in different cellular contexts, and the potency and limitations of crosstalk between the canonical and non -canonical NF[kappa]B pathways. Biochemistry and mathematical modeling are used to explore how the formation of NF[kappa]B dimers in MEFs and the importance of the interaction of the NF[kappa]B signaling network in MEFs and B-lymphocytes. Taken together, this work suggests that the cellular context, whether basally or undergoing stimulation, is critical in defining the NF[kappa]B dimer repertoire and its specific dimer activation. This specificity is important to consider when designing drugs to target a particular portion of the complex NF[kappa]B signaling network