UC San Diego

Nuclear factor kappa B (NFkappaB) transcription factors are responsible for the regulation of hundreds of target genes, their expression is induced by many classes of stimuli, and NFkappaBs play essential roles in the healthy regulation of cellular development and proliferation in inflammatory and immune responses. Diseases such as cancer, heart disease, Alzheimer's disease, and AIDS can be attributed to the aberrant regulation of NFkappaB. The transcriptional activity of NFkappaB is controlled by its inhibitors, the IkappaB, and IkappaBalpha in particular dynamically responds to extracellular stimuli releasing a burst of NFkappaB that enters the nucleus and activates target genes. The transcriptional activation is short- lived, and our lab is investigating the mechanism of post- induction repression. After a brief introduction (Chapter 1), I elucidate the role of the IkappaBalpha C-terminal PEST sequence in NFkappaB regulation and biophysically characterize the stabilized NFkappaB-DNA-IkappaBalpha ternary complex (Chapter 2), investigate the importance of IkappaBalpha-mediated regulation of NFkappaB in mouse embryonic fibroblast cells (Chapter 3), probe the coupled folding-upon-binding of IkappaBalpha in NFkappaB regulation (Chapter 4), and explore effect of DNA binding on NFkappaB stability and dynamics (Chapter 5). These studies suggest that the binding of IkappaBalpha and DNA to NFkappaB have widespread and powerful consequences on NFkappaB dynamics, function, and regulation