VEGF mRNA Expression Mechanisms in Hypoxia

缺氧时 VEGF mRNA 表达机制

基本信息

批准号：
7665558
负责人：
Kevin P. Claffey
金额：
$ 27.17万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-04-05 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7665558
关键词：
5&apos -AMP-activated protein kinase Affect Animals Binding Proteins Biological Breast Breast Cancer Cell Breast Cancer Model Breast Carcinoma Cell Survival Cells Colon Consumption Data Environment Event Experimental Models Genes Genetic Genetic Transcription Glioma Glycolysis Growth Factor Human Hypoxia Imaging Techniques In Vitro Individual Intervention Investigation Ligands Malignant Epithelial Cell Mammary Neoplasms Messenger RNA Mitogen-Activated Protein Kinases Modeling Neoplasm Metastasis Nuclear Export Nutrient Ovarian Pathway interactions Phosphorylation Post-Transcriptional Regulation Process Prostate Protein Isoforms Proteins RNA Interference RNA Transport RNA-Binding Proteins Receptor Signaling Regulation Repression Research Personnel Role Signal Pathway Signal Transduction Solid Neoplasm Stimulus Stress Technology Testing Therapeutic Therapeutic Intervention Translations Transplantation Transport Process Tumor Angiogenesis Tumor Expansion Vascular Endothelial Growth Factors Vascular Permeabilities angiogenesis cancer initiation cellular imaging deprivation ds RNA-Binding Proteins glucose uptake hypoxia inducible factor 1 in vivo mRNA Expression mRNA Stability malignant breast neoplasm neoplastic cell novel strategies novel therapeutic intervention programs protein complex protein expression response trafficking tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Hypoxic stimuli promote tumor cell survival, angiogenesis and breast cancer invasion. The expression of vascular endothelial growth factor (VEGF) requires hypoxia-induced transcription, mRNA stability, mRNA shuttling, protein translation and secretion. Secreted VEGF promotes local vascular permeability and angiogenesis, thus promoting tumor expansion and metastatic potential. We have identified two essential mechanisms that contribute to hypoxia-dependent VEGF expression: 1) post-transcriptional control of mRNA processing by double-stranded RNA-binding proteins, DRBP76 and ILF3, and 2) AMP-activated protein kinase a2 (AMPKa2) control of mRNA shuttling and translation. The central theme for this proposal is that tumor progression in hypoxic microenvironments requires AMPK signaling for VEGF expression and adaptive cell survival via post-transcriptional mechanisms and modulation of growth factor signaling pathways. Hypoxia-induced AMPK also represses mitogen activated protein kinase (MAPK) pathways in breast cancer cells, suggesting that systemic AMPK activation could repress breast cancer proliferation in vivo. These hypotheses will be tested in the following aims: Specific Aim 1 will define the role of double stranded RNA-binding proteins (DRBP76/ILF3) in hypoxia-induced VEGF mRNA stability, intracellular shuttling and translation and for biological relevance in experimental models of breast tumor progression, angiogenesis and metastasis. Specific Aim 2 will investigate the role of AMPKa2 isoform and AMPK signaling in controlling DRBP/ILF3 function in hypoxia-induced VEGF expression via post-transcriptional mechanisms and repression of MAPK signaling in breast cancer cells. Specific Am 3 will assess the role of AMPKa2 as a central regulator of human breast cancer progression, requirement for endogenous tumorigenesis and the potential for systemic AMPK activation as a novel therapeutic intervention for primary and metastatic breast cancer.

描述（由申请人提供）：缺氧刺激促进肿瘤细胞的存活，血管生成和乳腺癌侵袭。血管内皮生长因子（VEGF）的表达需要缺氧引起的转录，mRNA稳定性，mRNA穿梭，蛋白质翻译和分泌。分泌的VEGF促进局部血管渗透性和血管生成，从而促进肿瘤的扩张和转移潜力。我们已经确定了有助于缺氧依赖性VEGF表达的两种基本机制：1）通过双链RNA结合蛋白，DRBP76和ILF3对mRNA加工的转录后控制，以及2）AMP激活的AMP激活蛋白激酶A2（AMPKA2）对mRNA的控制和翻译。该建议的中心主题是低氧微环境中的肿瘤进展需要AMPK信号传导，以通过转录后机制和调节生长因子信号传导途径的调节来进行VEGF表达和自适应细胞存活。缺氧诱导的AMPK还抑制乳腺癌细胞中有丝分裂原活化蛋白激酶（MAPK）途径，这表明全身AMPK激活可以抑制体内乳腺癌的增殖。这些假设将在以下目的中进行测试：具体目标1将定义双链RNA结合蛋白（DRBP76/ILF3）在缺氧诱导的VEGF mRNA稳定性，细胞内穿梭和翻译以及在乳腺肿瘤进表的实验模型中的生物学相关性中的作用。具体的目标2将通过转录后的机制和抑制乳腺癌细胞中MAPK信号的抑制，研究AMPKA2同工型和AMPK信号传导在控制DRBP/ILF3功能中的作用。特定AM 3将评估AMPKA2作为人类乳腺癌进展的中心调节剂，内源性肿瘤发生的需求以及全身AMPK激活的潜力，作为对原发性和转移性乳腺癌的新型治疗干预措施。