Regulation of IL-12 Expression and Activity by Oncogenes

癌基因对 IL-12 表达和活性的调节

• 批准号: 6871371
• 负责人: XIAOJING MA
• 金额: $ 31万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871371
• 关键词: breast neoplasms; clinical research; dendritic cells; disease /disorder model; gene induction /repression; genetic regulation; human tissue; interleukin 12; laboratory mouse; macrophage; neoplasm /cancer genetics; neoplasm /cancer immunology; oncogenes; transcription factor

DESCRIPTION (provided by applicant): Immune competence is the most effective tool with which to control the growth of invasive tumors. Interleukin-12 (IL-12) is a molecule essential for the maintenance of this competency. IL-12 has powerful anti-tumor activities against many murine tumors as well as human cancers through its ability to activate NK, T cells, and macrophages, making it very difficult for tumors to escape from immune recognition and attack. The genes encoding the two heterologous chains of IL-12, p40 and p35 are located on different chromosomes. Together, p40 and p35 form the biologically active IL-12. The highly coordinated expression of p40 and p35 genes is pivotal for effective immune responses. The biosynthesis of IL-12 heterodimer is controlled by a complex network of immune-modulating activities. Tumor cells and their products that are etiologically associated with tumorigenesis can profoundly influence the response of the immune system that they interact with, e.g., IL-12 production and its bioactivities, potentially as means of evading immune surveillance and or thwarting its attack on the developing malignancy. Recent evidence has implicated two proto-oncogenes, c-Fos and c-Maf that are related basic leucine zipper transcription factors, as potential candidates in this category. The overall aim of this proposal is to understand how c-Fos and c-Maf interact with the immune system at cellular and molecular levels to exert their potent inhibitory effects on IL-12 production and its immunoregulatory activities as an intrinsic way of cancer cells to escape and retard adverse immune response to their growth and spread. We will: (1) Investigate the molecular mechanism by which c-Fos in the form of AP-1 regulates the production of IL-12 in macrophages and dendritic cells. (2) Determine the molecular basis of c-Maf-mediated inhibition of IL-12 gene expression, its interaction with AP- 1 in this activity, and its global impact on gene expression and function of antigen-presenting cells. (3) Test the hypothesis that inhibition of IL-12 production by AP-1 is contributory to tumor susceptibility in a murine mammary adenocarcinoma model. These studies will shed light on the strategies of cancer-inducing agents for the protection of cancer cells. They may also lead to discovery of novel pathways and identification of new targets for the benefit of immune interventions in cancer therapy.

描述（由申请人提供）：免疫能力是控制侵袭性肿瘤生长的最有效工具。白细胞介素-12 (IL-12) 是维持这种能力所必需的分子。 IL-12通过激活NK、T细胞和巨噬细胞的能力，对许多小鼠肿瘤以及人类癌症具有强大的抗肿瘤活性，使肿瘤很难逃脱免疫识别和攻击。编码IL-12的两条异源链p40和p35的基因位于不同的染色体上。 p40 和 p35 一起形成具有生物活性的 IL-12。 p40 和 p35 基因的高度协调表达对于有效的免疫反应至关重要。 IL-12 异二聚体的生物合成受免疫调节活性的复杂网络控制。与肿瘤发生有病因学相关的肿瘤细胞及其产物可以深刻地影响它们与之相互作用的免疫系统的反应，例如IL-12的产生及其生物活性，可能作为逃避免疫监视和/或阻止其攻击正在发育的免疫系统的手段。恶性肿瘤。最近的证据表明，与基本亮氨酸拉链转录因子相关的两种原癌基因 c-Fos 和 c-Maf 是此类中的潜在候选基因。该提案的总体目标是了解 c-Fos 和 c-Maf 如何在细胞和分子水平上与免疫系统相互作用，以发挥其对 IL-12 产生及其免疫调节活性的有效抑制作用，作为癌细胞消灭癌细胞的内在方式。逃避并延缓对其生长和传播的不良免疫反应。我们将：（1）研究AP-1形式的c-Fos调节巨噬细胞和树突状细胞中IL-12产生的分子机制。 (2)确定c-Maf介导的IL-12基因表达抑制的分子基础、其在该活性中与AP-1的相互作用、以及其对抗原呈递细胞的基因表达和功能的整体影响。 (3) 检验以下假设：AP-1 抑制 IL-12 的产生有助于小鼠乳腺癌模型中的肿瘤易感性。这些研究将揭示致癌剂保护癌细胞的策略。它们还可能导致新途径的发现和新靶点的识别，从而有利于癌症治疗中的免疫干预。