Molecular Mediators of Interferon induced Apoptosis

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DESCRIPTION (Provided by the Applicant): Interferons (IFNs) are multifunctional cytokines that have proved effective in treating hematologic and solid tumors. Regulation of gene expression within tumor cells by IFNs results in the antitumor effects for most tumor types. Antiproliferative and immunomodulatory effects have received the greatest focus as underlying cellular mechanisms of antitumor action of IFNs. However, cell loss contributes to antiproliferative effects of IFNs in the majority of tumor cell lines. In comparing the effects of IFN-B to those of IFN-a2, IFN-B was found to induce apoptosis in a broad range of tumor cell types. To identify genes that mediated IFN-dependent apoptosis, oligonucleotide gene array studies were performed using pooled RNA samples from sensitive WM-9 melanoma cells left untreated or treated with IFN-alpha-2 or IFN-beta for 8, 18 and 40 h. Those studies identified novel induced genes whose protein products are known, or hypothesized to regulate apoptotic processes including TNF-Related Apoptosis Inducing Ligand (TRAIL) and XIAP-associated factor-1 (XAF-1). Expression of these genes was correlated with IFN-beta induced apoptosis in sensitive, but not resistant cells. Studies aimed at affirming a functional role these proteins in mediating IFN-beta-dependent apoptotic responses are proposed. These include studies designed to neutralize TRAIL or XAF- 1 function in sensitive cells, and studies aimed at restoring their expression in unresponsive cells (Specific aims land 2). Although the phenomenon of IFN-beta-specific gene induction has been described in the literature, the mechanisms involved are poorly understood. The TRAIL gene will therefore be used as a tool to probe mechanisms of differential gene regulation by IFN-beta as compared to IFN-alpha (Specific aim 3). The results of these studies should provide important information on the molecular details of antitumor activity of IFNs that can be used to identify or develop targeted therapeutics that augment IFN effects.