Molecular Mediators of Interferon induced Apoptosis

描述（由申请人提供）：干扰素（IFN）是多功能的 细胞因子已被证明在治疗血液肿瘤和实体瘤中有效。 IFN对肿瘤细胞内基因表达的调节导致肿瘤细胞内的细胞凋亡。 对大多数肿瘤类型的抗肿瘤作用。抗增殖和免疫调节 影响已经得到最大的关注，作为潜在的细胞机制， IFN的抗肿瘤作用。然而，细胞损失有助于抗增殖 IFN在大多数肿瘤细胞系中的作用。在比较影响 IFN-α_2和IFN-β_2诱导细胞凋亡的作用与IFN-β诱导细胞凋亡的作用有显著的相关性。 一系列肿瘤细胞类型。 为了鉴定介导IFN依赖性细胞凋亡的基因， 使用来自敏感WM-9的合并RNA样品进行阵列研究 黑色素瘤细胞未处理或用IFN-α-2或IFN-β处理8，18 40 h。这些研究确定了新的诱导基因，其蛋白质产物 是已知的，或假设调节凋亡过程，包括 肿瘤坏死因子相关凋亡诱导配体（TRAIL）和XIAP相关因子-1 （XAF-1）。这些基因的表达与IFN-β诱导的 敏感细胞凋亡，但不耐药细胞凋亡。研究旨在确认 这些蛋白在介导IFN-β依赖性凋亡中的功能作用 提出了对策。这些研究包括旨在中和TRAIL或 XAF- 1在敏感细胞中的功能，以及旨在恢复其 在无反应细胞中的表达（具体目的和2）。虽然 IFN-β特异性基因诱导的现象已经在 文献中，所涉及的机制知之甚少。TRAIL基因将 因此可以作为一种工具来探测差异基因调控的机制 IFN-β与IFN-α相比（具体目标3）。的结果予以 研究应提供重要信息的分子细节， IFN的抗肿瘤活性，可用于鉴定或开发靶向 增强IFN效果的治疗剂。

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.