The ubiquitous transcription factor, NF-kB, stimulates the expression of a number of genes involved in immune responses, acute phase reactions, and viral infections. The large array of growth factors, cytokines, and viral proteins which activate kB-binding activity suggests that the NF-kB family may play a pivotal role in the regulation of such cellular processes as proliferation, differentiation, and programmed cell death. This proposal examines the mechanism(s) by which kB-binding activity is regulated in a cell cycle dependent manner. Preliminary studies suggest that the cytoplasmic inhibitor proteins of the IkB family which are normally associated with NF-kB, undergo site specific phosphorylations which alter their inhibitory activity.
Specific aims are designed to identify which components of the NF-kB and IkB families are being affected during cell cycle progression. In addition, experiments are suggested which address both the necessity and sufficiency of the kB factors in the transition into S phase. Studies suggest that a previously undescribed kinase activity which co-immunoprecipitates with the NF-kB/c-Rel complex might be responsible for the majority of phosphorylation events which regulate IkB activity. Goals are established to purify biochemically and to clone molecularly this Rel-associated kinase (RAK). Following IkB inactivation, the subsequent nuclear transport and DNA binding of the kB factors may be facilitated by a member of the heat shock protein family of chaperones.
Specific aims are proposed to characterize and to address the necessity of the presence of the hsc70 protein in the NF-kB complex. A mechanistic examination of the factors and signals which regulate NF-kB activity throughout cell cycle traverse will further our understanding of the events which effect not only normal growth and differentiation but the aberrant processes associated with autoimmune loss of tolerance, chronic infection, and neoplastic transformation.
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