VEGF mRNA Expression Mechanisms in Hypoxia

缺氧时 VEGF mRNA 表达机制

• 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
• 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' -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

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(申请人提供)：低氧刺激促进肿瘤细胞存活、血管生成和乳腺癌侵袭。血管内皮生长因子(VEGF)的表达需要低氧诱导的转录、mRNA的稳定性、mRNA的穿梭、蛋白质的翻译和分泌。分泌型血管内皮生长因子促进局部血管通透性和血管生成，从而促进肿瘤的扩张和转移潜能。我们已经确定了导致低氧依赖的VEGF表达的两个基本机制：1)双链RNA结合蛋白DRBP76和ILF3对mRNA加工的转录后控制，以及2)AMP激活的蛋白激酶a2(AMPKa2)控制mRNA的穿梭和翻译。这一提议的中心主题是，肿瘤在低氧微环境中的发展需要AMPK信号来表达血管内皮生长因子，并通过转录后机制和生长因子信号通路的调节来适应细胞生存。低氧诱导的AMPK还抑制乳腺癌细胞中的丝裂原活化蛋白激酶(MAPK)通路，提示全身AMPK激活可能抑制体内乳腺癌的增殖。这些假设将在以下目标中得到验证：特定目标1将确定双链RNA结合蛋白(DRBP76/ILF3)在低氧诱导的VEGF mRNA稳定、细胞内穿梭和翻译中的作用，以及在乳腺肿瘤进展、血管生成和转移的实验模型中的生物学相关性。目的2研究AMPKa2异构体和AMPK信号在低氧诱导的乳腺癌细胞中通过转录后机制和抑制MAPK信号通路调控DRBP/ILF3功能的作用。特定的AM 3将评估AMPKa2作为人类乳腺癌进展的中央调节因子的作用、内源性肿瘤发生的要求以及系统AMPK激活作为一种新的治疗原发和转移性乳腺癌的干预措施的可能性。