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在宿主免疫中起着重要作用，在治疗肿瘤和炎症性疾病方面有效。但是，其临床使用受到不良副作用的限制。因此，研究IFN生物学的研究的推动力之一是定义干扰素反应的组成部分，并利用它们提供IFN的治疗益处，而没有其相关的不良影响。尽管IFNG的大多数临床使用都是为了调节免疫学反应，而我们的兴趣是了解其与免疫相关的功能。随着意识到IFNG的影响是通过干扰素调节因素（例如IRF-1和ICSBP）介导的，因此，确定这些因素是否具有非免疫性相关功能，这是有意思的。我们以前曾通过将Sv40 t抗原（TAG）的表达靶向转基因小鼠的血管透镜，并用晶状体中IRF-1和ICSBP的本构激活来诱导透镜肿瘤。我们证明了通过IRF-1和ICSBP介导的非免疫机制来营救肿瘤表型。在这个财政年度，我们表征了基本机制，并表明它们是通过IFNG依赖性凋亡的激活和与p53或视网膜母细胞瘤蛋白的抑制作用而介导的。我们建立了镜头细胞线稳定地共表达TAG和IRF-1和ICSBP，对这些线的分析表明，它们的抗肿瘤效应是通过上调p21，p27，caspase 1的上调表达来介导的，并与TAG结合。综上所述，这些结果表明，利用IRF-1和ICSBP肿瘤抑制活性以提供IFNG的治疗益处而没有其相关的不良影响的可能性。