c-Myc transcription in intestinal growth, differentiation, and carcinogenesis

c-Myc 转录在肠道生长、分化和癌变中的作用

基本信息

项目摘要

DESCRIPTION (PROVIDED BY APPLICANT): The Wnt signaling pathway is essential for normal intestinal growth and development, and inappropriate activation of this pathway is associated with colorectal cancer. Wnt signaling causes nuclear accumulation of ¿-catenin, which then activates target genes involved in cell proliferation and growth. One such target is c- Myc, which also is required for normal intestinal cell differentiation. Therefore, understanding ¿-catenin regulation of c-Myc transcription is essential for elucidating both normal intestinal development and the pathogenesis of colorectal carcinoma. ¿-catenin activation of c-Myc is thought to occur through sequences located upstream from the c-Myc promoter. My findings, using an unbiased, genome-wide screen developed in our lab, indicate that a considerably more robust ¿-catenin binding site exists two kilobases downstream from the c-Myc transcriptional stop site. My preliminary results suggest that, in contrast to what is commonly believed, this 3' binding region provides the principal ¿-catenin regulation of c-Myc expression. Characterization of this element and its unique properties will provide new insights into c-Myc regulation. We will test whether this binding is functional by measuring the activities of reporter genes containing various combinations of mutations in the two 5' TCF binding sites and the 3' enhancer. Analysis of sequences surrounding the 3' element revealed predicted FOXO and AP-1 binding sites. I hypothesize that binding of AP-1 and/or a specific FOXO factor to the 3' site promotes a chromatin change that facilitates ¿-catenin binding. This will be tested by chromatin immunoprecipitation (ChIP) assays. To determine whether ¿-catenin associated with the 3' element interacts with factors bound to the 5' promoter region, we will perform chromatin conformation capture (CCC) assays. We will use a somatic cell genetic approach, using homologous recombination of an adeno-associated virus, to determine how the native 3' enhancer contributes to c-Myc expression in a colorectal carcinoma cell line. To eliminate the 3' enhancer specifically within the intestine, we will use Cre: LoxP technology, making use of a ¿-naphthoflavone-sensitive Cre recombinase under control of the intestine-specific CYP1A1 promoter. This mouse strain will allow us to assess the effects of deleting the 3' enhancer on c-Myc levels, intestinal cell migration, proliferation, and metabolism. PUBLIC HEALTH RELEVANCE: The regulation of c-Myc expression by ¿-catenin underlies fundamental growth processes in the intestine. Abnormalities in this pathway lead to colorectal cancer. Our studies address the fundamental mechanisms underlying b-catenin regulation of normal gastrointestinal development and homeostasis as well as the pathogenesis of intestinal malignancy.
描述(由申请人提供):Wnt 信号通路对于正常肠道生长和发育至关重要,该通路的不当激活与结直肠癌相关。 Wnt 信号传导导致 ¿-连环蛋白在核中积累,然后激活参与细胞增殖和生长的靶基因。其中一个靶标是 c-Myc,它也是正常肠细胞分化所必需的。因此,了解 β-catenin 对 c-Myc 转录的调节对于阐明正常肠道发育和结直肠癌的发病机制至关重要。 c-Myc 的 ¿-连环蛋白激活被认为是通过位于 c-Myc 启动子上游的序列发生的。我的研究结果表明,在我们实验室开发的无偏倚全基因组筛选中,c-Myc 转录终止位点下游两千碱基处存在一个更加强大的 ¿-连环蛋白结合位点。我的初步结果表明,与普遍认为的相反,这个 3' 结合区提供了 c-Myc 表达的主要 ¿-连环蛋白调节。该元素的表征及其独特的性质将为 c-Myc 调控提供新的见解。我们将通过测量两个 5' TCF 结合位点和 3' 增强子中包含各种突变组合的报告基因的活性来测试这种结合是否具有功能。对 3' 元件周围序列的分析揭示了预测的 FOXO 和 AP-1 结合位点。我推测 AP-1 和/或特定 FOXO 因子与 3' 位点的结合会促进染色质变化,从而促进 ¿-连环蛋白结合。这将通过染色质免疫沉淀 (ChIP) 检测进行测试。为了确定与 3' 元件相关的 ¿-连环蛋白是否与 5' 启动子区域结合的因子相互作用,我们将进行染色质构象捕获 (CCC) 测定。我们将使用体细胞遗传方法,利用腺相关病毒的同源重组,来确定天然 3' 增强子如何促进结直肠癌细胞系中的 c-Myc 表达。为了消除肠道内的 3' 增强子,我们将使用 Cre: LoxP 技术,利用 ¿-萘黄酮敏感的 Cre 重组酶,在肠道特异性 CYP1A1 启动子的控制下。该小鼠品系将使我们能够评估删除 3' 增强子对 c-Myc 水平、肠细胞迁移、增殖和代谢的影响。公共健康相关性:β-连环蛋白对 c-Myc 表达的调节是肠道基本生长过程的基础。该途径的异常会导致结直肠癌。我们的研究探讨了 β-连环蛋白调节正常胃肠道发育和稳态以及肠道恶性肿瘤发病机制的基本机制。

项目成果

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Gregory S. Yochum其他文献

899: TRANSCRIPTOME ANALYSIS IMPLICATES MYC AS A DRIVER OF EARLY ONSET COLORECTAL CANCER
  • DOI:
    10.1016/s0016-5085(22)60528-6
  • 发表时间:
    2022-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Olivia Marx;Marc Mankarious;Carli King;Wei Ding;Walter Koltun;Gregory S. Yochum
  • 通讯作者:
    Gregory S. Yochum
Tu1752 - Expression of Tristetraprolin in the Intestinal Epithelium Exacerbates DSS-Induced Colitis
  • DOI:
    10.1016/s0016-5085(18)33378-x
  • 发表时间:
    2018-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Melanie Eshelman;Emily Schleicher;Walter Koltun;Gregory S. Yochum
  • 通讯作者:
    Gregory S. Yochum
Su1783 - Accumulation of Cxcl10-Expressing CD163L1<sup>+</sup> Macrophages in the Sigmoid Colon of Diverticulitis Patients
  • DOI:
    10.1016/s0016-5085(18)34308-7
  • 发表时间:
    2018-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Kathleen M. Schieffer;Scott Emrich;Gregory S. Yochum;Walter Koltun
  • 通讯作者:
    Walter Koltun
11: BRD4-MK2 SIGNALING: TARGET FOR CROHN'S DISEASE-ASSOCIATED FIBROSIS.
  • DOI:
    10.1016/s0016-5085(22)60011-8
  • 发表时间:
    2022-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Marina Chulkina;Steven B. McAninch;Yi Li;Walter Koltun;Gregory S. Yochum;Bing Tian;Jia Zhou;Ellen J. Beswick;Allan R. Brasier;Iryna V. Pinchuk
  • 通讯作者:
    Iryna V. Pinchuk
Interferon-γ/Janus Kinase 1/STAT1 Signaling Represses Forkhead Box A1 and Drives a Basal Transcriptional State in Muscle-Invasive Bladder Cancer
γ-干扰素/Janus激酶1/信号转导及转录激活因子1信号通路抑制叉头框蛋白A1,并在肌层浸润性膀胱癌中驱动基础转录状态
  • DOI:
    10.1016/j.ajpath.2025.01.013
  • 发表时间:
    2025-05-01
  • 期刊:
  • 影响因子:
    3.600
  • 作者:
    Shamara S. Lawrence;Hironobu Yamashita;Lauren Shuman;Jay D. Raman;Monika Joshi;Gregory S. Yochum;Xue-Ru Wu;Hikmat A. Al-Ahmadie;Joshua I. Warrick;Vonn Walter;David J. DeGraff
  • 通讯作者:
    David J. DeGraff

Gregory S. Yochum的其他文献

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{{ truncateString('Gregory S. Yochum', 18)}}的其他基金

Wnt/beta-catenin signaling in early-onset colorectal cancer
早发性结直肠癌中的 Wnt/β-连环蛋白信号传导
  • 批准号:
    10648233
  • 财政年份:
    2023
  • 资助金额:
    $ 19.81万
  • 项目类别:
Dissecting the role of TCF7L1 in colorectal cancer
剖析 TCF7L1 在结直肠癌中的作用
  • 批准号:
    10040673
  • 财政年份:
    2020
  • 资助金额:
    $ 19.81万
  • 项目类别:
Nuclear AXIN2 and Colorectal Cancer
核 AXIN2 与结直肠癌
  • 批准号:
    9810856
  • 财政年份:
    2019
  • 资助金额:
    $ 19.81万
  • 项目类别:
c-Myc transcription in intestinal growth, differentiation, and carcinogenesis
c-Myc 转录在肠道生长、分化和癌变中的作用
  • 批准号:
    7759165
  • 财政年份:
    2008
  • 资助金额:
    $ 19.81万
  • 项目类别:
c-Myc transcription in intestinal growth, differentiation, and carcinogenesis
c-Myc 转录在肠道生长、分化和癌变中的作用
  • 批准号:
    8212456
  • 财政年份:
    2008
  • 资助金额:
    $ 19.81万
  • 项目类别:
c-Myc transcription in intestinal growth, differentiation, and carcinogenesis
c-Myc 转录在肠道生长、分化和癌变中的作用
  • 批准号:
    7612097
  • 财政年份:
    2008
  • 资助金额:
    $ 19.81万
  • 项目类别:
c-Myc transcription in intestinal growth, differentiation, and carcinogenesis
c-Myc 转录在肠道生长、分化和癌变中的作用
  • 批准号:
    8019464
  • 财政年份:
    2008
  • 资助金额:
    $ 19.81万
  • 项目类别:

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