Cytokine modulated model growth inhibitory mechanisms

细胞因子调节模型生长抑制机制

• 批准号: 8257946
• 负责人: DHAN V. KALVAKOLANU
• 金额: $ 26.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-07 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257946
• 关键词: Affect; Antiviral Agents; Apoptosis; Binding; Biological; Cell Line; Characteristics; Clinical; Clinical Research; Development; Family; Feedback; Functional disorder; Funding; Genes; Genetic; Growth; Growth Inhibitors; Growth Suppressor Genes; Human; Immune response; In Vitro; Interferons; Knockout Mice; Malignant Neoplasms; Modeling; Molecular; Mutation; Neoplasm Metastasis; Normal Cell; Oncogene Proteins; Oncogenes; Oncogenic; Physiological; Play; Primary Neoplasm; Process; Proteins; Regulatory Pathway; Retinoids; Role; Signal Transduction; Skin Carcinoma; Squamous cell carcinoma; Stat3 protein; System; Time; Transgenic Mice; Tretinoin; Tumor Suppression; Up-Regulation; Vitamin A; Xenograft Model; cell growth; cytokine; immune function; in vivo; in vivo Model; inhibitor/antagonist; mortality; neoplastic cell; new growth; novel; pathogen; response; transcription factor; tumor; tumor growth; viral DNA

DESCRIPTION (provided by applicant): Cytokines regulate neoplastic cell growth in vivo either by inducing the expression of growth suppressor genes in tumors or by mounting an immune response against them. The interferon family of cytokines regulates several physiologic responses such as antiviral, antitumor, and immune functions. By interacting with other cytokines, IFNs become an integral part of a large of intercellular signaling network that promotes anti-tumor and anti-pathogen surveillance system in vivo. In an earlier study, we demonstrated that the IFN-induced anti-tumor actions, especially apoptosis, could be synergistically augmented by all-trans retinoic acid (RA). This vitamin-A metabolite by itself acts as a growth inhibitor in many experimental and clinical models. Some clinical studies also demonstrated the potent tumor inhibitory effects of IFN/RA. We hypothesized that IFN/RA employs novel gene products for suppressing tumor growth. To identify the critical molecules involved in IFN/RA-induced apoptosis, we have used a genetic strategy and identified several Genes associated with Retinoid-Interferon-induced Mortality (GRIM). One such novel gene product, GRIM-19, suppresses growth via apoptosis. Previous studies by us and others showed that its activity suppressed by DNA viral oncoproteins and some cellular proteins. These observations indicate its potent anti-oncogenic characteristics. During the last funding period we have shown that GRIM-19 binds to Signal Transducer and Activator of Transcription 3 (STAT3) and suppresses its growth promoting action using cell line models. STAT3, a dormant cytokine-regulated transcription factor, is constitutively activated in a number of human tumors by oncogenic signals. STAT3 activity is regulated in normal cells by feedback inhibitors. Persistent STAT3 activity promotes survival, proliferation, metastasis of tumor cells by stimulating the expression of various cellular genes involved in those responses. Although oncogenic activation of STAT3 is an important step, we suggest that loss or inactivation of its inhibitors may also play a critical step in this process prior to the promotion of tumor growth. In preliminary studies, we showed that GRIM-19 suppress constitutive STAT3- induced tumor growth and metastasis using xenograft models. Consistent with these, we observed a loss of expression and mutations in GRIM-19 in several primary human tumors, which correlated with a strong upregulation of STAT3-inducible genes and promotion of cell growth. In this renewal application, we will investigate the biological relevance of GRIM-19 to tumor growth in vivo using knockout and transgenic mice. We will investigate the impact of grim19 mutations (found in primary tumors) on oncogene-induced tumor growth promotion using in vitro and in vivo models. Although a deregulation of STAT3 is known in many tumors, the molecular mechanisms of its deregulation, specifically the role of its inhibitors in tumor development are poorly studied. The studies proposed in this application will define how tumor- specific dysfunctions in GRIM-19 affect the functioning of this new growth regulatory pathway.

描述(由申请人提供)：细胞因子通过诱导肿瘤中生长抑制基因的表达或通过启动针对它们的免疫反应来调节体内肿瘤细胞的生长。干扰素家族的细胞因子调节多种生理反应，如抗病毒、抗肿瘤和免疫功能。通过与其他细胞因子的相互作用，IFN成为促进体内抗肿瘤和抗病原体监测系统的大量细胞间信号网络的组成部分。在早期的研究中，我们证明了全反式维甲酸(RA)可以协同增强干扰素诱导的抗肿瘤作用，特别是细胞凋亡。这种维生素A代谢物本身在许多实验和临床模型中起到了生长抑制的作用。一些临床研究也证明了干扰素/维甲酸具有很强的抑瘤作用。我们假设干扰素/RA使用新的基因产物来抑制肿瘤生长。为了确定与干扰素/维甲酸诱导的细胞凋亡相关的关键分子，我们采用了一种基因策略，并鉴定了几个与维甲酸干扰素诱导的死亡(GRIM)相关的基因。其中一种新的基因产物GRIM-19通过细胞凋亡抑制生长。我们和其他人之前的研究表明，它的活性受到DNA、病毒癌蛋白和一些细胞蛋白的抑制。这些观察表明，它具有很强的抗肿瘤作用。在过去的资助期间，我们通过细胞系模型显示GRIM-19与信号转导和转录激活因子3(STAT3)结合，并抑制其促进生长的作用。STAT3是一种休眠的细胞因子调节的转录因子，在许多人类肿瘤中通过致癌信号被结构性激活。在正常细胞中，STAT3的活性受反馈抑制剂的调节。持续的STAT3活性通过刺激参与这些反应的各种细胞基因的表达来促进肿瘤细胞的存活、增殖和转移。虽然STAT3的致癌激活是一个重要的步骤，但我们认为，在促进肿瘤生长之前，其抑制物的丢失或失活也可能在这一过程中发挥关键作用。在初步研究中，我们通过异种移植模型显示GRIM-19抑制结构性STAT3诱导的肿瘤生长和转移。与这些一致，我们观察到在几个原发人类肿瘤中GRIM-19的表达缺失和突变，这与STAT3诱导基因的强烈上调和促进细胞生长有关。在这一新的应用中，我们将使用基因敲除和转基因小鼠来研究GRIM-19与体内肿瘤生长的生物学相关性。我们将使用体外和体内模型研究Grim19突变(在原发肿瘤中发现)对癌基因诱导的肿瘤生长促进的影响。尽管STAT3的去调控在许多肿瘤中都是已知的，但其去调控的分子机制，特别是它的抑制物在肿瘤发展中的作用，研究得很少。这项申请中提出的研究将确定GRIM-19中肿瘤特异性功能障碍如何影响这一新的生长调节途径的功能。