Gene expression network for tumor suppression

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In the current study, we have made multifaceted approach to elucidate molecular mechanisms for oncogenesis, by analyzing not only the interrelationships between molecules which are involved in tumor suppression but also the gene expression network from both genetic and epigenetic aspects. Specifically, we found several important roles of "weak signal" by constitutively produced IFN-α/β in IFN-γ or IL-6-mediated cellular response as well as regulatory systems for cancer prevention. We also found a novel cross-talk mechanism between RANKL and IFN-γ, and clarified the regulatory role of the IFN system in osteoclast differentiation, which provided its putative therapeutic application to bone destruction by metastatic tumors. Development of autoimmune-like disease was observed in mice lacking IRF-2, which is an attenuator of IFN-a/β signaling. Further analyses revealed the role of IFN-α/β signaling in the regulation of CD8^+ T cell response. In these IRF-2-deficient mice, such hyperactivati … More on of IFN-α/β signaling affects normal differentiation of dendritic cells. IFN-α/β signaling is also found to be indispensable during DC maturation. Furthermore, it was demonstrated that another IRF-family member, IRF-7, is an essential transcriptional factor for the IFN induction in plasmacytoid DCs in response to unmethylated DNA (CpG), which is known to be a potent adjuvant for anti-tumor immunity. And we found a spaciotemporal regulation, by which plasmacytoid DCs are capable to produce IFN-α/β at high levels. On the other hand, IRF-5 is also found to be essentially involved in the CpG-induced production of proinflammatory cytokines. In addition, we identified novel p53 target genes, Noxa and Reprimo, which are involved in p53-mediated apoptosis or cell cycle arrest, respectively. Further study by generating Noxa-deficient mice revealed that Noxa may be a beneficial therapeutic target since it undergoes selective apoptosis in oncogene-expressing cells. Finally, we found an interrelationship between IFN-α/β signaling and p53-mediated response, which provided a novel aspect in terms of a linkage between tumor suppression and immunity.Taken together, we believe that these research accomplishments contribute to some advance in understanding molecular mechanisms underlying tumor suppression, and provide a molecular basis for their clinical applications. Less