This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Interleukin-1 receptor antagonists (IL-1Ra) are naturally occurring inhibitors of interleukin-1 (IL-1). Two intracellular forms of IL-1Ra (icIL-1Ra1 and icIL-1Ra3) have been described at the protein level. The precise function of these isoforms is unclear. Studies have demonstrated a role for icIL-1Ra1 as an inhibitor of IL-1-induced p38 MAP kinase activity, NFkB translocation, and IL-6 and IL-8 expression in epithelial cells. Previous data obtained from yeast two-hybrid analysis suggested that icIL-1Ra1 interacts with two intracellular proteins, COP9 signalosome subunit 3 (CSN3) and neuroblastoma amplified gene product (NAG). CSN3 is a component of the COP9 signalosome and its interaction with icIL-1Ra1 leads to an inhibition of CK2 and PKD kinases that associate with the signalosome complex. NAG is co-amplified along with MYCN in high grade neuroblastomas, however the normal function of the NAG protein is unknown. We hypothesize that icIL-1Ra1 and NAG play a crucial role in the regulation of cellular processes associated with IL-1 signaling. To address this hypothesis we initiated experiments examining the interaction of icIL-1Ra1 and NAG in relevant cell systems. Molecular tools were generated that allowed us to reconfirm the interaction of NAG and icIL-1Ra1 in relevant cell systems. Over-expression and knock-down expression systems have been designed and used to examine the effect of perturbing the expression of NAG and icIL-1Ra1 on global gene expression. Gene expression changes identified by microarray analysis have helped to identify candidate pathways linking NAG and icIL-1Ra1 to common physiological processes. The relevance of this linkage is currently under study.
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