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（由适用提供）：目标和假设：在癌症进展过程中，细胞遇到许多应力信号。如果无法修复，则具有内置机制来消除自己。成功的癌细胞设法挫败了这种硬有线应力反应。实际上，癌细胞似乎可以选择一些肿瘤补充剂成为癌基因。 TGF¿是展示这种“ Jekyll and Hyde”转换的最著名示例。 ATF3是一种可诱导的基因，是一种调节基因，最近被确定为在癌症进展中具有二分法作用：它在非转化的乳腺上皮细胞中是促凋亡的，但是保护恶性细胞免受压力免受压力并促进其转移。长期目的是使用ATF3作为解决此问题的处理方法来了解癌症二分法。将重点放在乳腺癌中ATF3的致癌方面。 AIM 1将检验以下假设：ATF3与TGF课程中一种蛋白质Smad3的相互作用在晚期乳腺癌细胞中ATF3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，包括域交换和定向诱变。 AIM 2将检验以下假设：ATF3至少部分通过调节下游靶基因在恶性细胞中发挥其致癌作用。潜在的靶启动子将通过染色质免疫沉淀测定和转录测定法测试，以确定它们是否是ATF3的直接靶基因。此外，将测试其调节的生物学意义。 AIM 3将检验以下假设：ATF3对于巨噬细胞的相互作用很重要。使用体外共培养和体内脂肪垫注射模型的功能丧失方法的增益和丧失方法都将测试ATF3是否在癌细胞与巨噬细胞相互作用的能力中起作用。意义：ATF3是一种新的调节剂，在癌症进展中具有二分作用，并且可能在基质癌的相互作用中起作用。由于它是由抗癌药引起的，因此其致癌功能表明这些药物可能具有不希望的作用。该提案的信息可能会为反癌症治疗的合理设计提供线索，从而有可能改变临床实践。公共卫生相关性：尽管早期发现和治疗方面取得了巨大进展，但一旦在区域淋巴结之外转移，乳腺癌就无法治愈。为了打击乳腺癌，必须更好地了解其转移。该提案调查了调节乳腺癌转移的主开关基因。