MODULATION OF IFN ACTION VIA NOVEL REGULATORY FACTORS

干扰素（IFN）是多功能细胞因子家族， 调节细胞抗肿瘤、抗病毒和免疫应答。他们 在临床上用于治疗人类癌症。 IFN的作用是 由IFN刺激基因（ISG）产物介导。 一些 转录因子通过Janus激酶信号被激活 转录激活因子（JAK-STAT）通路 用IFN刺激细胞。 在这些人中，有一个新兴的阶层， 称为IFN调节因子（IRF）的转录因子， 与癌蛋白myb在DNA结合域具有同源性。 间论坛 对于预防白血病，调节细胞凋亡， 细胞周期控制和淋巴细胞成熟。 P48，IRF家族 成员，是一种DNA结合因子，与STAT蛋白结合 在IFN处理的细胞中抑制肿瘤生长。 IFN-γ增强 通过增加p48基因对IFN-α/β的生物学反应 在多个细胞中表达。 在由显性病毒转化的细胞中， 由于p48的抑制， 基因编码p48的基因被IFN-γ以独特的方式调节 因为它具有一种新的IFN-γ应答元件， 结合已知的IFN调节因子。根据我们的初步研究， 假设IFN-γ调节p48表达是新介导的 因素 我们现在建议分离和表征编码 这些因素，并确定其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， 与参与细胞生长的调节因子家族有关 功能和预防肿瘤生长。 很可能突变 在这些基因产物中可能导致对干扰素治疗的抗性。 根据这些观察，我们预测这些因素可能是 不仅对调节干扰素作用而且对体内平衡都是必需的 宿主的防御 我们相信编码这些因子的基因的缺失 可能与人类癌症有关。 因此，它们可以作为标记， 监测导致这些疾病的突变。 这些基因可以 用于癌症的基因治疗，如果这样的突变基因是 发现了因此，描述以下行为的特征非常重要 这些新的因子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.