Mechanism of oncogenesis by Rel/NF-kappaB

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DESCRIPTION (provided by applicant): Rel/NF-kappaB proteins are transcription factors that play a central role in the regulation of cell proliferation, apoptosis, and immune responses. The altered or aberrant expression of Rel/NF-kappaB proteins is implicated in the pathology of human cancers derived from a variety of tissues, v-Rel, the acutely transforming member of this family, induces the rapid transformation of lymphocytes in vitro and in experimental animals. The v-Rel system has provided an excellent model to identify the mechanisms of oncogenesis by Rel/NF-kappaB proteins, v-Rel transforms cells by deregulating the expression of genes normally controlled by Rel/NF-kappaB family members. The identification and characterization of target genes differentially regulated by v-Rel will, therefore, provide insight into the molecular mechanisms by which Rel/NF-kappaB proteins function in tumorigenesis. Recent studies in this laboratory have identified a number of genes that are transcriptionally activated by v-Rel and whose expression contributes to the transformation process, ch-IAP1, a member of the inhibitor-of-apoptosis family, and IRF-4, an interferon regulatory factor, are upregulated in fibroblasts and lymphoid cells transformed by v-Rel. Expression of either protein enhances the ability of v-Rel to transform lymphocytes. By contrast, expression of ch-IAP1 or IRF-4 in the antisense orientation reduces the transforming ability of v-Rel. In addition to these proteins, Bcl-2 components and other members of the IRF family are differentially regulated by oncogenic Rel proteins. These proteins have established functions in the regulation of cell proliferation and apoptosis in lymphoid cells. The efficient transformation of cells by v-Rel appears to result from its ability to protect cells from apoptosis and interfere with the regulation of growth. The goals of this study are to define the mechanisms by which v-Rel target genes contribute to cell transformation. The role of ch-IAP1 in Rel-mediated transformation will be established by retrovirus-mediated gene expression and antisense techniques. The functional domains in ch-IAP1 required for its transforming and apoptosis-suppressing functions will be mapped, ch-IAP1 knockout B cell lines will be generated to define the requirement of this protein for the inhibition of apoptosis by v-Rel. Additional studies will define whether the differential activation of genes by v-Rel and a B cell tropic variant (S2A3v-Rel) can account for the target cell specificity of these oncogenes. Contributions of Bcl-2 and IRF family members to cell transformation by v-Rel and S2A3v-Rel will be defined. Finally, experiments will examine the mechanisms by which IRF-4 activates cell proliferation and extends the life span of cells transformed by v-Rel. These studies on the mechanisms of oncogenesis by v-Rel will provide insight into the contributions of Rel/NF-kappaB proteins in tumorigenesis.