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ATF3, a stress-inducible gene, in tumorigenesis and metastasis

ATF3，一种应激诱导基因，在肿瘤发生和转移中的作用

基本信息

批准号：
8081742
负责人：
TSONWIN HAI
金额：
$ 24.74万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8081742
关键词：
Address Affect Antineoplastic Agents Apoptotic Binding Binding Sites Biological Biological Assay Breast Breast Cancer Cell Breast Carcinoma Cells Cellular Stress Coculture Techniques EGF gene Early Diagnosis Early treatment Ectopic Expression Epidermal Growth Factor Receptor Epithelial Cells Epithelium Exhibits Fatty acid glycerol esters Figs - dietary Future Gene Activation Gene Targeting Genes Genetic Transcription Goals Health In Vitro Injection of therapeutic agent Intervention Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Modeling Mutation Neoplasm Metastasis Oncogenes Oncogenic Pathway interactions Pharmaceutical Preparations Play Proteins Recruitment Activity Regulation Regulator Genes Role Signal Transduction Site-Directed Mutagenesis Snails Stress Structure Switch Genes TWIST1 gene Testing Tumor Suppressor Proteins biological adaptation to stress cancer cell cancer therapy cell motility chromatin immunoprecipitation clinical practice combat design in vivo loss of function lymph nodes macrophage malignant breast neoplasm mutant paracrine promoter protein complex repaired research study response tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Goal and Hypothesis: During cancer progression, the cells encounter many stress signals. If beyond repair, the cells have built-in mechanisms to eliminate themselves. The successful cancer cells managed to foil this hardwired stress response. In fact, it appears that cancer cells can co-opt some tumor suppressors to become oncogenes. TGF¿ is the best-known example exhibiting this "Jekyll and Hyde" conversion. ATF3, a stress- inducible gene, is a regulatory gene that was recently identified to have a dichotomous role in cancer progression: it is pro-apoptotic in non-transformed breast epithelial cells, but protects the malignant cells from stress and promotes their metastasis. The long-term objective is to understand the cancer dichotomy using ATF3 as a handle to address this issue. This proposal will focus on the oncogenic aspect of ATF3 in breast cancer. Aim 1 will test the hypothesis that the interaction of ATF3 with Smad3, a protein in the TGF¿ pathway, plays an important role in the oncogenic activity of ATF3 in advanced breast cancer cells. This will be tested by structure-function analyses, including domain swap and site-directed mutagenesis. Aim 2 will test the hypothesis that ATF3 exerts its oncogenic action in malignant cells, at least in part, by regulating downstream target genes. Potential target promoters will be tested by chromatin immunoprecipitation assay and transcription assay to determine whether they are the direct target genes of ATF3. In addition, the biological significance of their regulation by ATF3 will be tested. Aim 3 will test the hypothesis that ATF3 is important for macrophage-cancer interaction. Both gain- and loss- of-function approaches, using in vitro co-culture and in vivo fat pad injection models, will be taken to test whether ATF3 plays a role in the ability of cancer cells to interact with macrophages. Significance: ATF3 is a new regulator that has a dichotomous role in cancer progression, and may play a role in stroma-cancer interaction. Because it is induced by anti-cancer drugs, its oncogenic function indicates that these drugs may have undesired effects. Information from the proposal may provide clues for rational designs of anti-cancer treatment, thus potentially changing the clinical practice in the future. PUBLIC HEALTH RELEVANCE: Despite the tremendous advances in early detections and treatments, breast cancer becomes incurable once metastasized beyond the regional lymph nodes. Thus, to combat breast cancer, it is essential to better understand its metastasis. This proposal investigates a master switch gene that regulates breast cancer metastasis.

描述(申请人提供)：目标和假设：在癌症进展过程中，细胞遇到许多应激信号。如果无法修复，这些细胞有内置的机制来消除自己。成功的癌细胞成功地挫败了这种固有的应激反应。事实上，癌细胞似乎可以选择一些肿瘤抑制基因来成为癌基因。转化生长因子？是展示这种“Jekyll and Hyde”转换的最著名的例子。ATF3是一种应激诱导基因，是一种调节基因，最近被发现在癌症进展中具有二分性作用：在未转化的乳腺上皮细胞中，它是促凋亡的，但它保护恶性细胞免受应激的影响，并促进其转移。我们的长期目标是理解使用ATF3作为句柄来解决这个问题的癌症二分法。这项提案将集中在ATF3在乳腺癌中的致癌方面。目的1验证ATF3与转化生长因子途径蛋白Smad3的相互作用在晚期乳腺癌细胞ATF3致癌活性中的重要作用。这将通过结构-功能分析进行测试，包括结构域交换和定点突变。目的2将验证ATF3至少部分地通过调节下游靶基因在恶性肿瘤细胞中发挥致癌作用的假设。潜在的靶启动子将通过染色质免疫沉淀试验和转录试验进行检测，以确定它们是否是ATF3的直接靶基因。此外，还将测试ATF3对它们的调控的生物学意义。目的3将验证ATF3在巨噬细胞-肿瘤相互作用中的重要作用这一假设。使用体外共培养和体内脂肪垫注射模型，采用获得和功能丧失的方法，将被用来测试ATF3是否在癌细胞与巨噬细胞相互作用的能力中发挥作用。意义：ATF3是一种新的调节因子，在癌症进展中具有二分性作用，并可能在间质-癌症相互作用中发挥作用。由于它是由抗癌药物诱导的，其致癌作用表明这些药物可能会有不良影响。该提案的信息可能为抗癌治疗的合理设计提供线索，从而可能改变未来的临床实践。公共卫生相关性：尽管在早期发现和治疗方面取得了巨大进步，但一旦乳腺癌转移到区域淋巴结以外，就变得无法治愈。因此，为了对抗乳腺癌，更好地了解其转移是至关重要的。这项提案研究了一种调节乳腺癌转移的主开关基因。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The bZIP repressor proteins, c-Jun dimerization protein 2 and activating transcription factor 3, recruit multiple HDAC members to the ATF3 promoter.

DOI：
10.1016/j.bbagrm.2012.09.005
发表时间：
2012-11
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
影响因子：
4.7
作者：
Darlyuk-Saadon, Ilona;Weidenfeld-Baranboim, Keren;Yokoyama, Kazunari K.;Hai, Tsonwin;Aronheim, Ami
通讯作者：
Aronheim, Ami

PDE-constrained multispectral imaging of tissue chromophores with the equation of radiative transfer.