MODULATION OF IFN ACTION VIA NOVEL REGULATORY FACTORS

干扰素(干扰素)是一个多功能细胞因子家族， 调节细胞抗肿瘤、抗病毒和免疫反应。他们 临床上用于治疗人类癌症。干扰素的作用是 由干扰素刺激基因(ISG)产物介导。一批 转录因子通过Janus激酶信号被激活 转导转录激活因子(JAK-STAT)途径 用干扰素刺激细胞。在这些人中，有一个新兴的阶层 转录因子称为干扰素调节因子(IRF)，它 与癌蛋白MYB在其DNA结合区显示同源性。IRFS 对于预防白血病，调节细胞凋亡， 细胞周期调控和淋巴细胞成熟。P48，一个IRF家族 是一种与STAT蛋白相关的DNA结合因子 抑制干扰素处理细胞中的肿瘤生长。干扰素-γ增强 P48基因上调对干扰素-α/β的生物学效应 在多个单元格中表达。在显性病毒转化的细胞中 癌基因，干扰素反应被抑制，因为抑制P48 吉恩。编码p48的基因由干扰素-γ以一种独特的方式进行调节 因为它拥有一种新的干扰素-伽马反应元件，而不是 结合已知的干扰素调节因子。根据我们的初步研究，我们 假设干扰素-γ调节P48的表达是新的 各种因素。我们现在建议分离和鉴定编码基因 这些因素决定了它们在细胞生长抑制中的作用。 初步研究表明，这些因素是不同的，但 与参与细胞生长的调节因子家族有关 肿瘤生长的功能和预防。突变很可能是 这些基因产物中可能会导致对干扰素治疗的耐药性。 基于这样的观察，我们预测这些因素可能是 不仅对调节干扰素的作用是必不可少的，而且对体内平衡也是必不可少的 宿主防御系统。我们认为编码这些因子的基因丢失 可能与人类癌症有关。因此，它们可以作为标记 监测导致此类疾病的突变。这些基因可能是 对癌症的基因治疗很有用，如果这些突变的基因 被发现了。因此，重要的是要描述 这些新的因素及其在生长控制中的作用。

Interferons (IFN) are a family of multifunctional cytokines that modulate the cellular antitumor, antiviral and immune responses. They are in clinical use for the therapy of human cancers. IFN actions are mediated by IFN stimulated gene (ISG) products. A number of transcription factors are activated though the Janus Kinase-Signal Transducing Activators of Transcription (JAK-STAT) pathway upon stimulation cells with IFNs. Among these is a burgeoning class of transcription factors called the IFN regulatory factors (IRF) which exhibit homology to oncoprotein myb in their DNA binding domains. IRFs are essential for the prevention of leukemia, regulation of apoptosis, cell cycle control and lymphocyte maturation. P48, an IRF family member, is a DNA binding factor which in association with STAT proteins inhibits tumor growth in IFN-treated cells. IFN-gamma enhances biological responses to IFN-alpha/beta through an increase in p48 gene expression in several cells. In cells transformed by dominant viral oncogenes, IFN responses are inhibited because of repression of p48 gene. The gene encoding p48 is modulated in a unique manner by IFN-gamma because it possesses a novel IFN-gamma response element which does not bind known IFN-regulated factors. Based on our preliminary studies we hypothesize that IFN-gamma modulated expression of p48 is mediated novel factors. We now propose to isolate and characterize the genes encoding these factors and determine their role in cell growth inhibition. Preliminary studies indicate that these factors are distinct but are related to families of regulatory factors involved in cell growth function and prevention of tumor growth. It is likely that mutations in these gene products may contribute to resistance to IFN-therapy. Based on such observations we predict that these factors may be essential not only for regulating IFN-action but also for homeostasis of host defenses. We believe that loss of genes encoding these factors may be linked to human cancers. Thus they may serve as markers for monitoring mutations leading to such diseases. These genes may be useful for genetic therapy of cancer, if such mutated genes are discovered. Therefore, it is important to characterize the actions of these novel factors and their role in growth control.