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.

干扰素在宿主免疫中发挥重要作用，对肿瘤和炎症性疾病有较好的治疗效果。然而，其临床应用受到不良副作用的限制。因此，干扰素生物学研究背后的驱动力之一是定义干扰素反应的成分，并利用它们来提供干扰素的治疗益处，而不会产生相关的不良反应。尽管IFNG的大多数临床应用是为了调节免疫反应，我们感兴趣的是了解它的非免疫相关功能。随着对干扰素调节因子如IRF-1和ICSBP等干扰素调节因子作用的认识，确定这些因子是否具有非免疫相关功能是很有意义的。我们以前曾通过靶向表达SV40T抗原(Tag)到我们的转基因小鼠的无血管晶状体上，并在晶状体中结构性激活IRF-1和ICSBP来诱导晶状体肿瘤。我们展示了IRF-1和ICSBP介导的非免疫机制对肿瘤表型的挽救作用。在本财年，我们描述了潜在的机制，并表明它们是通过激活依赖于IFNG的细胞凋亡和抑制TAG与P53或视网膜母细胞瘤蛋白的相互作用来调节的。我们建立了稳定共表达TAG、IRF-1和ICSBP的晶状体细胞系，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、caspase1的表达并与TAG结合来实现的。综上所述，这些结果表明，利用IRF-1和ICSBP的肿瘤抑制活性可以提供IFNG的治疗益处，而不会产生相关的不良反应。