Interferon-inducible Transcription Factors: Roles In Ocu

干扰素诱导转录因子：在 Ocu 中的作用

• 批准号: 6507394
• 负责人: Charles E Egwuagu
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6507394
• 关键词: antineoplastics; apoptosis; cell line; cysteine endopeptidases; eye neoplasms; gene expression; genetically modified animals; interferon gamma; intermolecular interaction; laboratory mouse; lens disorder; neoplasm /cancer genetics; neoplasm /cancer immunology; neoplasm /cancer remission /regression; neoplastic growth; p53 gene /protein; retinoblastoma protein; simian virus 40; transcription factor; tumor antigens; tumor suppressor proteins

IFNg plays important roles in host immunity and is efficacious in the treatment of neoplastic and inflammatory diseases. However, its clinical use is limited by undesirable side effects. One of the driving forces behind research on the biology of IFNs has therefore been to define components of the interferon response and exploit them to provide therapeutic benefits of IFN without its associated adverse effects. Although most clinical use of IFNg has been to modulate immunological responses and our interest is in understanding its non-immunity related functions. With the realization that effects of IFNg are mediated through interferon regulatory factors such as IRF-1 and ICSBP, it was of interest to determine whether these factors have non-immunity related function. We had previously induced lens neoplasia by targeting expression of SV40 T Antigen (TAg) to the avascular lens of our transgenic mice with constitutive activation of IRF-1 and ICSBP in the lens. We demonstrated rescue of the neoplastic phenotype by non-immunological mechanisms mediated by IRF-1 and ICSBP. In this fiscal year we characterized the underlying mechanism and show that they are mediated by activation of IFNg-dependent apoptosis and inhibition of TAg interactions either with p53 or retinoblastoma protein. We established lens cells lines stably co-expressing TAg and either IRF-1 and ICSBP and analysis of these lines revealed that their anti-tumor effects are mediated by up-regulating expression of p21, p27, caspase 1 and binding to TAg. Taken together, these results suggest the potential of exploiting the tumor suppressive activities of IRF-1 and ICSBP to provide therapeutic benefits of IFNg without its associated adverse effects.

IFNg在宿主免疫中起重要作用，并且在肿瘤和炎性疾病的治疗中是有效的。然而，其临床应用受到不良副作用的限制。因此，IFN生物学研究背后的驱动力之一是定义干扰素应答的组分，并利用它们来提供IFN的治疗益处而没有其相关的副作用。尽管IFNg的大多数临床用途是调节免疫应答，但我们的兴趣是了解其非免疫相关功能。随着IFNg的作用通过干扰素调节因子如IRF-1和ICSBP介导的认识，确定这些因子是否具有非免疫相关功能是令人感兴趣的。我们先前通过将SV 40 T抗原（TAg）靶向表达到我们的转基因小鼠的无血管透镜诱导透镜瘤形成，并在透镜中组成性激活IRF-1和ICSBP。我们证明了通过IRF-1和ICSBP介导的非免疫机制拯救肿瘤表型。在本财政年度，我们的特点的基本机制，并表明，它们是由激活IFNg依赖性细胞凋亡和抑制TAg相互作用与p53或视网膜母细胞瘤蛋白介导的。我们建立了稳定共表达TAg和IRF-1或ICSBP的透镜细胞系，并对这些细胞系的分析表明，它们的抗肿瘤作用是通过上调p21、p27、caspase 1的表达并与TAg结合介导的。总之，这些结果表明，利用IRF-1和ICSBP的肿瘤抑制活性来提供IFNg的治疗益处而没有其相关的不良反应的潜力。