Molecular Mediators of Interferon induced Apoptosis

说明(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病和实体肿瘤方面有效。 IFN对肿瘤细胞内基因表达的调节导致 对大多数肿瘤类型都有抗肿瘤作用。抗增殖和免疫调节作用 作为潜在的细胞机制，其影响受到了最大的关注 干扰素的抗肿瘤作用。然而，细胞丢失有助于抗增殖。 干扰素在大多数肿瘤细胞系中的作用在比较效果时 干扰素-B与干扰素-α2相比，干扰素-B可诱导广泛的细胞凋亡。 肿瘤细胞类型的范围。 确定介导干扰素依赖的细胞凋亡的基因，寡核苷酸基因 使用来自敏感的WM-9的混合RNA样本进行阵列研究 黑色素瘤细胞未处理或用干扰素-α-2或干扰素-β处理8，18 和40小时。这些研究发现了新的诱导基因，其蛋白产物 已知或被假设为调节细胞凋亡过程，包括 肿瘤坏死因子相关凋亡诱导配体与XIAP相关因子-1 (XAF-1)。这些基因的表达与干扰素-β诱导的 敏感细胞中的细胞凋亡，但不是抗性细胞。旨在肯定一项 这些蛋白在介导干扰素依赖的细胞凋亡中的功能作用 并提出了相应的对策。这些研究包括旨在中和TRAIL或 XAF-1在敏感细胞中发挥作用，旨在恢复其功能的研究 在无反应细胞中表达(特异性靶点LAND 2)。尽管 干扰素-β特异性基因诱导现象已在 文献中，对其中涉及的机制知之甚少。TRAIL基因将 因此可作为探索差异基因调控机制的工具 通过干扰素-β与干扰素-α(特定目标3)进行比较。这些研究的结果 研究应该提供关于分子细节的重要信息 可用于识别或开发靶向的干扰素的抗肿瘤活性 增强干扰素效应的治疗方法。

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.