Distinct functions of negative regulators of NF-kappaB.

摘要

The Nuclear Factor kappaB (NF-kappaB) signaling pathway is central to cellular responses to a diverse set of stimuli and stresses. It has been shown that much of this pleiotropic capacity is encoded within the activation dynamics of the upstream IkappaB Kinase (IKK), which acts as a central hub for NF-kappaB signaling. To account for how regulatory mechanisms impart specific NF-kappaB dynamics in response to IKK activity, I utilized a multidisciplinary approach that integrated mechanistic mathematical modeling with laboratory experimentation. Herein, I describe four pair wise comparisons between NF-kappaB inducible IkappaBalpha protein, the predominant regulatory mechanism, with others mediated by IkappaBbeta, IkappaBepsilon, IkappaBdelta and A20. IkappaBepsilon and A20 are shown to primarily regulate the second phase of TNF responsive NF-kappaB activity by dampening oscillatory behavior and tuning the amplitude, respectively. Differences in inducible synthesis and stimulus-responsive degradation kinetics are determined to impart specific functionalities for IkappaBalpha and IkappaBdelta negative feedback in acute/inflammatory versus chronic/pathogenic NF-kappaB signaling. In the final study, the role of IkappaBbeta, a constitutive regulator, is delineated as mediating the distribution of RelA/NF-kappaB dimers in the resting cell but not their dynamics following cellular stimulation. These studies reveal the individual role of each mechanism, and collectively, the sources and functionalities of the emergent systems properties observed in cells in which these regulators act combinatorially.