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Mechanism of angiogenin-induced angiogenesis

血管生成素诱导血管生成的机制

基本信息

批准号：
8472447
负责人：
GUO-FU HU
金额：
$ 25.19万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8472447
关键词：
Address Amino Acids Amyotrophic Lateral Sclerosis Animal Model Animals Antibodies Antineoplastic Agents Apoptosis Binding Binding Sites Biological Biological Process Cell Death Cell Nucleolus Cell Nucleus Cell Proliferation Cell Surface Receptors Cell Survival Cells Code Cytoplasmic Granules Cytoskeleton Destinations Embryo Endocytosis Fibroblasts Funding Genes Genetic Genetic Transcription Goals Growth Human Internal Ribosome Entry Site Knock-out Knockout Mice Legal patent Ligands Malignant Neoplasms Malignant neoplasm of prostate Maps Mediating Messenger RNA Molecular Target Monoclonal Antibodies Mus Neomycin Nerve Degeneration Neurodegenerative Disorders Nuclear Translocation Nude Mice Oncogenic Paper Patients Peptides Phosphorylation Play Predisposition Production Promoter Regions Prostate Protein Array Analysis Proteins Proto-Oncogene Proteins c-akt Receptor Signaling Ribonucleases Ribosomal DNA Ribosomal RNA Role Semaphorins Signal Pathway Signal Transduction Small Interfering RNA Small RNA Stress Testing Therapeutic Transcription Process Transfer RNA Transgenic Animals Transgenic Mice Transgenic Organisms Translations Tumor Angiogenesis Work Xenograft procedure angiogenesis angiogenin angiogenin receptor autocrine biological adaptation to stress cancer cell cell growth chemical carcinogen drug development inhibiting antibody inhibitor/antagonist intraepithelial knock-down loss of function mutation novel overexpression paracrine research study response tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Angiogenin (ANG) is a 14 kDa angiogenic ribonuclease that is upregulated in a variety of human cancers. Loss-of-function mutations in the coding region of ANG have recently been found in patients with amyotrophic lateral sclerosis (ALS). Studies carried out in the previous funding period have demonstrated an important role of ANG in ribosomal RNA (rRNA) synthesis, which is essential for many fundamental biological processes including cell growth, proliferation, and survival. We have created conditional Ang1 knockout mice and have shown that Ang1 null mice have reduced angiogenic response and increased susceptibility to stress-induced apoptosis. Mechanistically, we have demonstrated that the biological activity of ANG relies on its subcellular destination. Under growth condition, ANG is translocated to the nucleus where it stimulates ribosomal RNA (rRNA) transcription and processing thereby promoting cell growth and proliferation. Under stress, ANG is translocated to the stress granules where it enhances the production of tiRNA (tRNA-derived, stress-induced small RNA) that reprogram protein translation thereby promoting cell survival. We have also identified PlexinB2 as a functional ANG receptor that is both necessary and sufficient for mediating biological activity of ANG. We have shown that ANG and Semaphorin 4C (Sema4C), the other ligand of PlexinB2, bind at non-overlapping regions and trigger different signals. The objective of this proposal is to understand the mechanism of action of ANG in stimulating angiogenesis and cancer progression. This objective will be achieved by addressing the following four specific aims. (1) Assess the therapeutic activity of anti-ANG receptor (PlexinB2) antibody. We will examine the effect of anti-PlexinB2 monoclonal antibodies on angiogenesis and tumor progression in both xenograft and transgenic animal models. (2) Characterize the differential effect of ANG and Sema4C in angiogenesis and tumor progression. We will assess the effect of knockdown PlexinB2 and Sema4C on Akt- induced prostate intraepithelial (PIN) and compare the results with that from ANG knockdown. (3) Determine the role of ANG in stress-regulated protein translation and cell survival. We will identify the signals that direct translocation of ANG into stress granules and into nucleus. We will also characterize the role of ANG-mediated tiRNA in reprogramming protein translation and promoting cell survival. (4) Characterize the effect of Ang1 knockout and ANG overexpression in angiogenesis and tumor growth. We will examine the function of ANG in cancer susceptibility to oncogenic insults inflicted by environmental and genetic factors. We will also study autocrine vs. paracrine action of ANG and their respective contributions toward tumor angiogenesis and cancer cell proliferation. We anticipate that the results of these experiments will elucidate how ANG interacts with its cell surface receptor, how the signaling pathway is transduced, and how ANG promotes cell survival and proliferation. These results will provide a comprehensive understanding of the function and mechanism of ANG in angiogenesis and in cancer progression.

描述（由申请人提供）：血管生成素（ANG）是一种 14 kDa 的血管生成核糖核酸酶，在多种人类癌症中表达上调。最近在肌萎缩侧索硬化症 (ALS) 患者中发现了 ANG 编码区的功能丧失突变。上一资助期进行的研究证明了 ANG 在核糖体 RNA (rRNA) 合成中的重要作用，这对于包括细胞生长、增殖和生存在内的许多基本生物过程至关重要。我们创建了条件性 Ang1 基因敲除小鼠，并证明 Ang1 缺失小鼠的血管生成反应减少，对应激诱导的细胞凋亡的敏感性增加。从机制上讲，我们已经证明 ANG 的生物活性依赖于其亚细胞目的地。在生长条件下，ANG 易位至细胞核，刺激核糖体 RNA (rRNA) 转录和加工，从而促进细胞生长和增殖。在压力下，ANG 被转移到压力颗粒，在那里它增强了 tiRNA（tRNA 衍生的、压力诱导的小 RNA）的产生，从而重新编程蛋白质翻译，从而促进细胞存活。我们还发现 PlexinB2 是一种功能性 ANG 受体，它对于介导 ANG 的生物活性是必要且充分的。我们已经证明 ANG 和 Semaphorin 4C (Sema4C)（PlexinB2 的另一个配体）在非重叠区域结合并触发不同的信号。该提案的目的是了解 ANG 在刺激血管生成和癌症进展中的作用机制。这一目标将通过解决以下四个具体目标来实现。 (1)评估抗ANG受体(PlexinB2)抗体的治疗活性。我们将在异种移植和转基因动物模型中研究抗 PlexinB2 单克隆抗体对血管生成和肿瘤进展的影响。 (2) 表征 ANG 和 Sema4C 在血管生成和肿瘤进展中的不同作用。我们将评估敲低 PlexinB2 和 Sema4C 对 Akt 诱导的前列腺上皮内 (PIN) 的影响，并将结果与 ANG 敲低的结果进行比较。 (3)确定ANG在应激调节蛋白翻译和细胞存活中的作用。我们将识别引导 ANG 易位到应激颗粒和细胞核中的信号。我们还将描述 ANG 介导的 tiRNA 在重编程蛋白质翻译和促进细胞存活中的作用。 (4) 表征Ang1敲除和ANG过表达对血管生成和肿瘤生长的影响。我们将研究 ANG 在癌症对环境和遗传因素造成的致癌损伤的易感性中的功能。我们还将研究 ANG 的自分泌与旁分泌作用以及它们各自对肿瘤血管生成和癌细胞增殖的贡献。我们预计这些实验的结果将阐明ANG如何与其细胞表面受体相互作用、信号通路如何转导以及ANG如何促进细胞存活和增殖。这些结果将提供对 ANG 在血管生成和癌症进展中的功能和机制的全面了解。