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: 7183574
• 负责人: XIAOJING MA
• 金额: $ 29.39万
• 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/7183574
• 关键词: Anabolism; Antigen-Presenting Cells; Breast Adenocarcinoma; Categories; Chromosomes; Competence; Complex; Data; Dendritic Cells; FOS gene; Gene Expression; Genes; Growth; Host Defense; Human; Immune; Immune response; Immune system; Immunologic Surveillance; Immunologics; Interleukin-12; Interleukin-12 Gene; Intervention; Invasive; Lead; Light; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Oncogenes; Pathway interactions; Predisposition; Production; Proto-Oncogenes; Regulation; System; T-Lymphocyte; Testing; Transcription Factor AP-1; bZIP Domain; base; cancer cell; cancer therapy; cytokine; macrophage; neoplastic cell; novel; pathogen; pressure; response; tool; transcription factor; tumor; tumorigenesis

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）：免疫能力是控制侵入性肿瘤生长的最有效工具。白介素12（IL-12）是维持这种能力必不可少的分子。 IL-12具有激活NK，T细胞和巨噬细胞的能力，具有强大的抗肿瘤活性以及对许多鼠类癌症的强大抗肿瘤活性，这使得肿瘤很难摆脱免疫识别和攻击。编码IL-12，p40和p35的两个异源链的基因位于不同的染色体上。 P40和P35一起形成了生物活性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由复杂的免疫调节活性网络控制。肿瘤细胞及其与肿瘤发生相关的肿瘤细胞及其产物可以深刻影响与IL-12的产生及其生物活性相互作用的免疫系统的反应，这可能是逃避免疫监测的手段，或者避免其对发展恶性肿瘤的攻击。最近的证据暗示了与基本亮氨酸拉链转录因子相关的两种原始基因，C-FOS和C-MAF是该类别的潜在候选者。该提案的总体目的是了解C-FOS和C-MAF如何与细胞和分子水平下的免疫系统相互作用，以对IL-12产生及其免疫调节活性产生有效的抑制作用，以作为癌细胞逃避和延迟对其生长和扩散的癌细胞的内在方式。我们将：（1）研究以AP-1形式的C-FOS调节巨噬细胞和树突状细胞中IL-12的产生的分子机制。 （2）确定C-MAF介导的IL-12基因表达抑制的分子基础，其与AP-1在该活性中的相互作用以及其对抗原呈递细胞的基因表达和功能的全球影响。 （3）检验以下假设：在鼠类乳腺癌模型中，AP-1抑制IL-12产生是肿瘤易感性的。这些研究将阐明癌细胞诱导癌细胞的策略。它们还可能导致发现新的途径并确定新靶标，以造福癌症治疗中的免疫干预措施。