Signal-induced processing of the nfkb2 gene product, pl00, is a critical mechanism of NF-kB regulation. The full-length pl00 functions as a potent inhibitor of NF-kB, sequestering various NF-kB members in the cytoplasm. Upon processing, the C-terminal half of pl00 is degraded by the proteasome, leading to generation of an active NF-kB component, p52, which is required for peripheral B cell growth and function and the formation of germinal centers in lymphoid organs. Emerging evidence suggests that defect in p52 generation causes deficiencies in humeral immune responses, while overproduction of p52 or the loss of intact pl00 is associated with abnormal lymphocyte growth and development of lymphoid malignancies. Since the processing of pl00 serves to both generate p52 and interrupt the inhibitory function of pl00, deregulation of this proteolytic event may have profound effect on lymphocyte growth and function. The overall objective of this application is to understand the molecular mechanism regulating pl00 processing. This knowledge is important for rational development of strategies and therapies to modulate immune responses and treat lymphoid malignancies. We have recently shown that the processing of pl00 is tightly suppressed by its C-terminal sequences and that the active pl00 processing can be induced through its phosphorylation and ubiquitination. Based on these findings, we hypothesize that the signal for constitutive pl00 processing is normally masked by its negative-regulatory sequences and that the inducible processing of pl00 is triggered by its site-specific phosphorylation and ubiquitination. To accomplish the objective of this application, we will pursue four specific aims: (i) define the negative- and positive-regulatory sequences of pl00 processing; (ii) identify and characterize cellular factors regulating the processing of pl00; (iii) investigate how the GRR regulates pl00 processing; (iv) investigate pl00 processing in vivo using transgenic mice.
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