Functional role of p68 tyrosine phosphorylation in cancer metastasis

p68 酪氨酸磷酸化在癌症转移中的功能作用

• 批准号: 7487547
• 负责人: Zhi-Ren Liu
• 金额: $ 21.96万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487547
• 关键词: ATP phosphohydrolase; Antibodies; Biological Assay; Boxing; Cancer Patient; Cancer cell line; Cancerous; Cell Nucleus; Cell Polarity; Cells; Cessation of life; Chimeric Proteins; Colon Carcinoma; Complex; Condition; Cytoplasm; Deacetylation; Development; Diagnosis; Disseminated Malignant Neoplasm; DsRed; Epithelial; Epithelial Cells; Event; Genes; Genetic Transcription; Goals; HDAC1 gene; HT29 Cells; Human; Immunoblotting; Implant; Lead; Left; Localized; Malignant Neoplasms; Mediating; Mesenchymal; Modeling; Molecular; Monitor; Morphology; Neoplasm Metastasis; NuRD complex; Nuclear; Nuclear Translocation; Nude Mice; Organ; Pathway interactions; Phosphorylation; Platelet-Derived Growth Factor; Play; Process; Property; Proteins; RNA Helicase; Research Personnel; Research Proposals; Role; Snails; Staining method; Stains; Testing; Tissue Sample; Tissues; Tyrosine; Tyrosine Phosphorylation; Up-Regulation; Xenograft procedure; beta catenin; cancer cell; design; enhanced green fluorescent protein; heterokaryon; mouse model; mutant; neoplastic cell; novel; outcome forecast; programs; promoter; protein p68; protein protein interaction; research study; snail protein; tumor progression

DESCRIPTION (provided by applicant): We have: observed that p68 RNA helicase acquired substantially higher level of phosphorylation(s) at tyrosine residues in both metastatic cancer cell lines and tissue samples compared to that in non-metastatic cancer cell lines and tissue samples. P68 is not phosphorylated in non-cancerous tissues. We also found that phosphorylation of p68 at tyrosine 593 is required for epithelial-mesenchymal-transition (EMT), a critical event for cancer metastasis. The phosphorylated p68 promotes EMT by facilitating beta-catenin nuclear translocation and activating transcription of Snail gene. Our hypothesis is that the phosphorylated p68 is a new and important regulatory factor that plays important role(s) in promoting EMT and tumor progression/metastasis. The goals of this research proposal are two fold: (1) to gain a comprehensive understanding of the molecular mechanism by which the phospho-p68 promotes EMT, and (2) to extensively test the role of the phospho-p68 in promoting cancer metastasis. In specific aim 1, we propose experiments to test the role of the p68 phosphorylation in promoting cancer metastasis both in xenograft mice model and in tissue samples from cancer patients. In specific aim 2, we design experiments to elucidate the mechanism by which the phospho-p68 activates Snail gene transcription. We will test whether the phospho- p68 use its protein-dependent ATPase activity to 'displace' HDAC1 from remodeling and deacetylation complex (NuRD) at Snail promoter. Most cancer-related deaths are the consequence of the cancer metastasis. Although an outline picture about the process of cancer metastasis is emerge, the detailed mechanism is still far beyond fully understanding, especially the cellular factors that contribute to each steps of cancer metastasis. In specific aim 3, we propose experiments to test whether the phospho-p68 actively 'transports' cytoplasmic beta-catenin to the nucleus. Our study will uncover a new molecular factor that is involved in cancer metastasis. Understanding the functional role of phospho-p68 will ultimately be applied to develop new strategies to the diagnosis/prognosis and treatment for cancer metastasis.

描述（由申请人提供）：我们有：观察到，在转移性癌细胞系和组织样品中，P68 RNA解旋酶在酪氨酸残基上获得了较高水平的磷酸化水平，而不是在非中性癌细胞系和组织样品中。 p68在非癌组织中未磷酸化。我们还发现，上皮 - 间质转换（EMT）需要p68在酪氨酸593处的磷酸化，这是癌症转移的关键事件。磷酸化的p68通过促进β-catenin核易位并激活蜗牛基因的转录来促进EMT。我们的假设是，磷酸化的p68是一种新的重要调节因素，在促进EMT和肿瘤进展/转移中起重要作用。该研究建议的目标是两个方面：（1）对磷酸-P68促进EMT的分子机制的全面了解，以及（2）广泛测试磷酸-P68在促进癌症转移中的作用。在特定目标1中，我们提出了实验，以测试p68磷酸化在异种移植小鼠模型中促进癌症转移和癌症患者的组织样本中的作用。在特定目标2中，我们设计了实验，以阐明磷酸-P68激活蜗牛基因转录的机制。我们将测试磷酸p68是否使用其蛋白质依赖性ATPase活性来从蜗牛启动子上的重塑和脱乙酰化复合物（NURD）中“位移” HDAC1。大多数与癌症有关的死亡是癌症转移的结果。尽管出现了有关癌症转移过程的轮廓图，但详细的机制仍然远远超出了完全理解的范围，尤其是导致癌症转移步骤的每个步骤的细胞因素。在特定的目标3中，我们提出了实验，以测试磷酸-P68是否会主动将胞质β-catenin“转运”到核中。我们的研究将发现与癌症转移有关的新分子因子。了解磷酸-P68的功能作用最终将用于制定新的策略，以诊断/预后和治疗癌症转移。