NF-kappaB N-myc in Oncogenic Pathways of the CNS

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DESCRIPTION (provided by applicant): Dr. Raquel Sitcheran is conducting postdoctoral work in the laboratory of Dr. Albert Baldwin at the University of North Carolina, with the long-term career goal of becoming an independent scientist in an academic environment. Dr. Sitcheran's research is directed at elucidating how the transcription factor NF-KB responds to diverse extracellular signals to control fundamental processes, such as cell proliferation, apoptosis and malignant transformation. Because NF-KB can promote cell survival through anti-apoototic mechanisms, anti-cancer drugs targeting inhibition NF-KB activity can improve the efficacy of chemotherapy treatments. However, NF-KB can also promote cell death by repressing cell survival pathways. Similarly, the N-myc oncogene, which is frequently amplified in aggressive neuroblastoma, can both promote and antagonize cell survival. Therefore, efficacious cancer therapies cannot be achieved simply by targeting inhibition of NF-KB or N-mvc. It is of utmost importance to understand how NF-KB and N-myc are regulated by diverse signals to specify activation or repression of target genes, thereby facilitating the design of anticancer drugs that selectively target NF-KB and/or N-mvc functions. Preliminary data suggest that 1) NF-KB and N-myc can interact in vivo and 2) N-myc can repress the activity of NF-KB. Given the important, and sometimes opposing, roles that NF-KB and N-myc play in regulating cell survival and oncogenesis, Dr. Sitcheran's immediate goals are to gain additional training in the use of proteomics, microarray and mouse model systems to evaluate the biological significance of the interaction between NF-KB and N-myc and the mechanism by which Nmyc represses NF-KB. This proposal will elucidate how NF-KB responds to diverse developmental, physiological and pathological signals to specify unique patterns of gene expression. The following Specific Aims will be investigated: 1) Characterization of the NF-KB:N-myc protein complex; 2) Investigation of the mechanism by which N-myc regulates NF-KB activity 3) Identification and characterization of genes regulated by both N-myc and NF-KB; and 4)Analysis of cooperativity between N-myc and NF-KB in neuroblastoma pathogenesis. These studies have the potential to offer new insight into drug design targeting oncogenic pathways regulated by NF-KB and N-myc.