A Novel Mechanism for LEF1 Promoter Regulation in Colon Cancer

结肠癌中 LEF1 启动子调控的新机制

基本信息

  • 批准号:
    8718884
  • 负责人:
  • 金额:
    $ 5.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-15 至 2016-09-14
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): In the United States, colon cancer is the third leading cause of cancer-related deaths with African-Americans having a higher incidence and mortality rate than any other ethnicity. This year, the American Cancer Society estimates that 102,480 Americans will be diagnosed with colon cancer and of those cases, 50,830 individuals will succumb to the disease. To date, colorectal cancer is the most notorious cancer linked to overactive, aberrant Wnt signaling. Most cases derive from inactivating mutations in the adenomatous polyposis coli gene, which encodes a key component of the b-catenin Destruction Complex. The increase in stable, cytoplasmic, b- catenin results in an influx of this regulator int the nucleus where it works with Lymphoid Enhancer Factor/T Cell Factors (LEF/TCFs) to activate transcription of Wnt target genes, such as CMYC and LEF1. The LEF1 locus contains two promoters. Promoter 1 (P1), which is a Wnt target, produces full-length Lymphoid Enhancer Factor-1 (FL-LEF-1), an isoform that works with b-catenin: promoter 2 (P2) produces dominate negative LEF-1 (dnLEF-1), an isoform that lacks the b-catenin binding domain, and can therefore down-regulate Wnt target genes. Importantly, only the Wnt-targeted FL-LEF-1 isoform is expressed in colon cancer. The dnLEF-1 producing P2 promoter is actively silenced by an unknown mechanism involving an upstream repressor element and the multifunctional protein, Yin Yang 1 (YY1). Since re-introduction of dnLEF-1 can oppose Wnt signaling by binding to Wnt target genes for downregulation, it is important to elucidate the mechanism of its transcriptional repression and determine how this regulator can be re-expressed in cancer. The following aims and methods are proposed: 1) Determine whether YY1 uses an RNA-dependent mechanism to silence P2. RNA immunoprecipitation assays and in vitro biochemical approaches are proposed. 2) Define the nucleotide context and associated proteins of the upstream repressor element. A transient transfection assay for repression will be used to define the core sequences within the element. DNA affinity chromatography and mass spectrometry will identify proteins interacting with these key sequences 3) Test the hypothesis that transcription from upstream P1 affects transcriptional activity of downstream P2. P1 transcription will be modulated using a custom designed TALE-repressor. Defining the mechanism of P2 repression will lead to a better understanding of expression from multi-promoter gene loci, and thus highlight the potential for broad impact and new therapeutic approaches in cancer and other diseases.
描述(由申请人提供):在美国,结肠癌是癌症相关死亡的第三大原因,非裔美国人的发病率和死亡率高于任何其他种族。美国癌症协会估计,今年将有 102,480 名美国人被诊断患有结肠癌,其中 50,830 人将死于该病。迄今为止,结直肠癌是与过度活跃、异常的 Wnt 信号传导有关的最臭名昭著的癌症。大多数病例源自腺瘤性息肉病大肠杆菌基因的失活突变,该基因编码 b-连环蛋白破坏复合物的关键成分。稳定的细胞质 b-连环蛋白的增加导致该调节因子流入细胞核,在细胞核中与淋巴增强因子/T 细胞因子 (LEF/TCF) 一起激活 Wnt 靶基因(例如 CMYC 和 LEF1)的转录。 LEF1 基因座包含两个启动子。启动子 1 (P1) 是 Wnt 靶标,可产生全长淋巴增强因子-1 (FL-LEF-1),这是一种与 b-连环蛋白一起作用的同种型:启动子 2 (P2) 产生主导阴性 LEF-1 (dnLEF-1),这是一种缺乏 b-连环蛋白结合域的同种型,因此可以下调 Wn​​t 靶基因。重要的是,只有 Wnt 靶向的 FL-LEF-1 亚型在结肠癌中表达。产生 dnLEF-1 的 P2 启动子被一种未知机制主动沉默,该机制涉及上游阻遏元件和多功能蛋白 Yin Yang 1 (YY1)。由于重新引入 dnLEF-1 可以通过与 Wnt 靶基因结合进行下调来对抗 Wnt 信号传导,因此阐明其转录抑制机制并确定该调节因子如何在癌症中重新表达非常重要。提出以下目标和方法:1)确定YY1是否使用RNA依赖性机制来沉默P2。提出了 RNA 免疫沉淀测定和体外生化方法。 2) 定义上游阻遏元件的核苷酸背景和相关蛋白。抑制的瞬时转染测定将用于定义元件内的核心序列。 DNA 亲和层析和质谱将鉴定与这些关键序列相互作用的蛋白质 3) 检验上游 P1 的转录影响下游 P2 的转录活性的假设。 P1 转录将使用定制设计的 TALE 抑制子进行调节。定义 P2 抑制机制将有助于更好地了解多启动子基因位点的表达,从而突出其在癌症和其他疾病中产生广泛影响和新治疗方法的潜力。

项目成果

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