Analysis of anti-growth properties of processed Follistatin proteins

加工后的卵泡抑素蛋白的抗生长特性分析

• 批准号: 7252974
• 负责人: THEODOR E HAERRY
• 金额: $ 21.38万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252974
• 关键词: Activins; Adrenal Gland Neoplasms; Animals; Binding; Biological; Blood; Cachexia; Cancer Etiology; Cell Proliferation; Cells; Code; Complex; Development; Drosophila genome; Drosophila genus; Drosophila held out wings protein; Engineering; Exhibits; Extracellular Protein; Family; Financial compensation; Follistatin; Generations; Genetic Recombination; Goals; Growth; Growth Factor; Growth Inhibitors; Human; Ligands; Link; Malignant Neoplasms; Mass Spectrum Analysis; Modeling; Molecular Weight; Mus; Mutant Strains Mice; Mutate; Mutation; N Domain; Numbers; Pathway interactions; Process; Property; Protein Binding; Proteins; Signal Transduction; Structure; Subgroup; Testing; Tissues; Wasting Syndrome; Work; fly; inhibin; inhibitor/antagonist; loss of function; loss of function mutation; member; mutant; prevent; receptor; research study; tumor; tumor progression

DESCRIPTION (provided by applicant): Members of the TGF-b family of growth factors (Activins/Inhibins/BMPs) are extracellular proteins that provide important signals during animal development. Mutations in many components of the TGF-b pathway have been linked to the loss of growth control and tumor formation in humans. In mice, the loss of Inhibin-a results in gonadal and adrenal tumors followed by a cancer cachexia-like wasting syndrome. These mice exhibit more than tenfold elevated levels of Activin in the blood suggesting that it may cause or facilitate the development or the progression of these cancers. It was found that ubiquitous over-expression of the Activin inhibitor Follistatin (FS) in inhibin-a mutant mice reduces Activin levels, alleviates cachexia, and prolongs survival. However, FS was not potent enough to prevent the formation of these tumors. Interestingly, we found that Drosophila Follistatin (dFS) is a stronger growth inhibitor than its vertebrate orthologues. Compared to vertebrate FS proteins, dFS is larger, more basic, and proteolytically processed. Our results suggest a model, where processed forms of dFS not only bind and inhibit ligands but also block signaling by allowing the formation of inactive complexes with type II receptors. To test this hypothesis, we will isolate, identify, and generate processed forms of dFS and analyze their biological activity. The final goal of the proposed work is to engineering modified FS proteins with greater anti-growth properties that could be used to combat cancers caused by mutations in Inhibin-a and other TGF-b signaling components. Follistatins are secreted proteins that bind members of the TGF-b family and inhibit cell proliferation. The final goal of the proposed work is to engineering modified FS proteins with greater anti-growth properties that could be used to combat cancers caused by mutations in TGF-b signaling components.

描述（由申请人提供）：生长因子TGF-β家族成员（激活素/抑制素/BMP）是在动物发育期间提供重要信号的细胞外蛋白。TGF-β通路的许多组分的突变与人类生长控制和肿瘤形成的丧失有关。在小鼠中，Inhibin-a的缺失导致性腺和肾上腺肿瘤，随后是癌症恶病质样消耗综合征。这些小鼠在血液中表现出超过十倍的激活素水平，表明它可能导致或促进这些癌症的发展或进展。发现激活素抑制剂卵泡抑素（FS）在白细胞介素-α突变小鼠中的普遍过表达降低了激活素水平，减少了恶病质和小鼠存活。然而，FS不足以有效地防止这些肿瘤的形成。有趣的是，我们发现果蝇卵泡抑素（dFS）是一个更强的生长抑制剂比它的脊椎动物直系同源物。与脊椎动物FS蛋白相比，dFS更大，更碱性，并且经过蛋白水解处理。我们的研究结果提出了一个模型，其中处理形式的dFS不仅结合和抑制配体，而且通过允许与II型受体形成非活性复合物来阻断信号传导。为了验证这一假设，我们将分离、鉴定和生成dFS的加工形式，并分析其生物活性。拟议工作的最终目标是工程改造具有更大抗生长特性的修饰FS蛋白，可用于对抗由抑制素-a和其他TGF-b信号传导组分突变引起的癌症。卵泡抑素是结合TGF-β家族成员并抑制细胞增殖的分泌蛋白。拟议工作的最终目标是工程改造具有更大抗生长特性的修饰FS蛋白，可用于对抗由TGF-b信号传导成分突变引起的癌症。