The mechanism of angiogenin-induced angiogenesis

血管生成素诱导血管生成的机制

• 批准号: 7069117
• 负责人: GUO-FU HU
• 金额: $ 29.42万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069117
• 关键词: angiogenesis; angiogenesis factor; carcinogenesis; cell line; chromatin immunoprecipitation; clinical research; genetic transcription; genetically modified animals; histones; human genetic material tag; laboratory mouse; neoplasm /cancer blood supply; neoplastic growth; prostate neoplasms; ribosomal DNA; ribosomes

DESCRIPTION (provided by applicant): Angiogenin is an angiogenic ribonuclease that is upregulated in a variety of cancer cells. It undergoes nuclear translocation in endothelial cells and in various cancer cells but not in normal fibroblasts and epithelial cells. Nuclear angiogenin has been shown to stimulate rRNA transcription, a rate-limiting step for ribosome biogenesis. Preliminary studies have shown that knocking-down angiogenin expression in endothelial cells decreases rRNA transcription and abolishes cell proliferation stimulated by a number of angiogenic proteins including aFGF, bFGF, EGF, and VEGF. Down-regulating angiogenin in cancer cells reduces rRNA transcription, cell proliferation, and tumorigenicity. Blockade of nuclear translocation of angiogenin inhibits angiogenesis and xenografic growth of human tumor cells on nude mice. Therefore, angiogenin seems to play an important role in modulating rRNA transcription and may be a general requirement for angiogenesis and tumor growth regardless of the nature of the growth stimuli. The objective of this proposal is to characterize this unconventional mechanism of rRNA transcription regulation mediated by angiogenin in the process of angiogenesis and tumor growth. This proposal has four specific aims. First, the role of angiogenin in VEGF-dependent tumor angiogenesis and tumor growth will be characterized in a xenografic mouse model. Second, the role of angiogenin in Akt-induced prostate cancer development will be examined in the transgenic mice that over-express Akt in the prostate. Third, binding of angiogenin to rDNA will be characterized in vivo by ChIP to determine whether and how this interaction enhances promoter occupancy and rRNA transcription. Fourth, angiogenin-mediated inhibition of histone H3 methylation will be analyzed and the effect of angiogenin on nucleosomal structure and chromatin remodeling will be characterized. Based on the compelling preliminary results, the proposed studies are likely to reveal a novel mechanism by which angiogenin regulates rRNA transcription in the orchestrated event of ribosome biogenesis during angiogenesis and tumor growth.

描述（由申请人提供）：血管生成素是一种在多种癌细胞中上调的血管生成核糖核酸酶。它在内皮细胞和各种癌细胞中发生核转位，但在正常成纤维细胞和上皮细胞中不发生核转位。核血管生成素已显示刺激rRNA转录，这是核糖体生物合成的限速步骤。 初步研究表明，敲低内皮细胞中的血管生成素表达会降低rRNA转录，并消除由许多血管生成蛋白（包括aFGF、bFGF、EGF和VEGF）刺激的细胞增殖。下调癌细胞中的血管生成素可降低rRNA转录、细胞增殖和致瘤性。阻断血管生成素核转位抑制人肿瘤细胞裸鼠移植瘤的血管生成和生长。因此，血管生成素似乎在调节rRNA转录中起重要作用，并且可能是血管生成和肿瘤生长的一般要求，而不管生长刺激的性质如何。本提案的目的是描述在血管生成和肿瘤生长过程中由血管生成素介导的rRNA转录调节的非常规机制。这项建议有四个具体目标。首先，血管生成素在VEGF依赖性肿瘤血管生成和肿瘤生长中的作用将在异种移植小鼠模型中表征。第二，血管生成素在Akt诱导的前列腺癌发展中的作用将在前列腺中过表达Akt的转基因小鼠中进行检查。第三，将在体内通过ChIP表征血管生成素与rDNA的结合，以确定这种相互作用是否以及如何增强启动子占用和rRNA转录。第四，将分析血管生成素介导的组蛋白H3甲基化抑制，并表征血管生成素对核小体结构和染色质重塑的影响。基于令人信服的初步结果，拟议的研究可能揭示一种新的机制，血管生成素调节rRNA转录的核糖体生物合成的精心策划的事件在血管生成和肿瘤生长。