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

• 批准号: 7646445
• 负责人: TSONWIN HAI
• 金额: $ 25.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7646445
• 关键词: Address; Affect; Antineoplastic Agents; Apoptotic; Binding; Binding Sites; Biological; Biological Assay; Breast; Breast Cancer Cell; Breast Cancer Treatment; Breast Carcinoma; Cells; Cellular Stress; Coculture Techniques; Early Diagnosis; 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; 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; TP53 gene; 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; public health relevance; repaired; research study; response; tumor; tumor progression; tumorigenesis

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（由申请人提供）：目标和假设：在癌症进展期间，细胞遇到许多应激信号。如果无法修复，细胞有内在的机制来消除自己。成功的癌细胞设法挫败了这种硬连线的压力反应。事实上，癌细胞似乎可以选择一些肿瘤抑制因子成为致癌基因。转化生长因子是最著名的例子展示这种“化身博士”转换。ATF 3是一种应激诱导基因，是一种调节基因，最近被鉴定为在癌症进展中具有二分作用：它在非转化的乳腺上皮细胞中促凋亡，但保护恶性细胞免受应激并促进其转移。长期目标是使用ATF 3作为解决这个问题的手柄来理解癌症二分法。该提案将集中于乳腺癌中ATF 3的致癌方面。目的1将检验以下假设：ATF 3与Smad 3（TGF β通路中的一种蛋白质）的相互作用在晚期乳腺癌细胞中ATF 3的致癌活性中起重要作用。这将通过结构-功能分析进行测试，包括结构域交换和定点诱变。目的2将检验ATF 3在恶性细胞中至少部分通过调节下游靶基因发挥其致癌作用的假设。将通过染色质免疫沉淀试验和转录试验检测潜在的靶启动子，以确定它们是否是ATF 3的直接靶基因。此外，还将测试ATF 3对其调节的生物学意义。目的3将检验ATF 3对巨噬细胞-癌症相互作用重要的假设。使用体外共培养和体内脂肪垫注射模型的功能获得和功能丧失方法将用于测试ATF 3是否在癌细胞与巨噬细胞相互作用的能力中起作用。意义：ATF 3是一种新的调节因子，在癌症进展中具有二分作用，并可能在基质-癌症相互作用中发挥作用。因为它是由抗癌药物诱导的，它的致癌功能表明这些药物可能有不希望的效果。该提案中的信息可能为合理设计抗癌治疗提供线索，从而可能改变未来的临床实践。公共卫生关系：尽管在早期检测和治疗方面取得了巨大进展，但乳腺癌一旦转移到区域淋巴结以外就无法治愈。因此，为了与乳腺癌作斗争，必须更好地了解其转移。这项提议调查了一个调节乳腺癌转移的主开关基因。