Inhibition of Migration by ATE+31

ATE 31 抑制迁移

• 批准号: 7234757
• 负责人: EUGENE G LEVIN
• 金额: $ 38.14万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7234757
• 关键词: Acids; Address; Adhesions; Amino Acids; Animal Model; Animals; Biological Factors; Breast Carcinoma; Carcinoma; Cell Proliferation; Corneal Neovascularization; Cultured Cells; Deletion Mutagenesis; Development; Disease regression; Evolution; Exposure to; Fibroblast Growth Factor 2; Filament; Focal Adhesion Kinase 1; Focal Adhesions; Growth Factor; Immigration; In Vitro; Malignant Epithelial Cell; Malignant Neoplasms; Microfilaments; Molecular Weight; Neoplasm Metastasis; Peptides; Personal Satisfaction; Phosphorylation; Phosphorylation Inhibition; Phosphotransferases; Positioning Attribute; Rate; Site; Testing; Therapeutic; Therapeutic Uses; Tumor Angiogenesis; Vascular blood supply; cell growth; cell motility; in vivo; lung Carcinoma; migration; mouse model; response; tumor; tumor growth

DESCRIPTION (provided by applicant): The high molecular weight form of FGF-2 (24kDa FGF-2) is produced by alternative translational start sites and consists of the more commonly studied 18kDa FGF-2 with an additional 55 amino acids at the amino terminal end. Treatment of endothelial or breast carcinoma cells with 24kDa FGF-2 results in an 80% decrease in migration rate although it continues to promote cell proliferation. We have performed deletion mutagenesis and developed a truncated form of 24kD FGF-2 which is highly effective in inhibiting migration in vitro while having no effect on cell growth. This peptide consists of the amino terminal 86 amino acids of 24kD FGF-2 and is referred to as ATE+31. Studies in animals have shown that ATE+31 is highly effective in suppressing mammary carcinoma and lung carcinoma tumor growth by two mechanisms, suppressing the angiogenic response and inhibiting tumor cell migration away from the tumor core. Studies of the mechanism by which ATE+31 inhibits migration have revealed that growth factor-induced increases in focal adhesion kinase (FAK) phosphorylation are abrogated by ATE+31. The decrease in phosphorylation occurred at tyr397 ,tyr407, and tyr861. Concomitantly, exposure to ATE+31 inhibited the reorganization of micro filaments and loss of focal adhesions that accompany growth factor treatment making enhanced motility difficult to attain. The hypothesis that this project will address states that ATE+31 inhibits cell migration through a mechanism involving the suppression of FAK function through inhibition of enhanced phosphorylation. The project will examine the mechanism by which ATE-31 inhibits cell migration and employ animal models to test the in vitro results in vivo. Specifically the project will define the mechanisms by which ATE+31 suppresses FAK phosphorylation and how it subsequently inhibits focal adhesion/rnicrofi lament dynamics and employ mouse models of angiogenesis and tumor development to test the experimental results in vivo. In addition, the therapeutic potential of ATE+31 will be evaluated in animal models of tumor development, regression, and metastasis will be evaluated.

描述(申请人提供)：高分子量形式的成纤维细胞生长因子-2(24kDa成纤维细胞生长因子-2)是由不同的翻译起始点产生的，由通常研究较多的18kDa成纤维细胞生长因子-2组成，在氨基末端有另外55个氨基酸。用24 kDa的成纤维细胞生长因子-2处理内皮细胞或乳腺癌细胞，尽管它继续促进细胞的增殖，但其迁移率降低了80%。我们进行了缺失突变，并开发出一种截短形式的24kD成纤维细胞生长因子-2，它在体外高效地抑制迁移，而对细胞生长没有影响。该肽由24kD的成纤维细胞生长因子-2的86个氨基酸组成，称为ATE+31。动物实验表明，ATE+31通过两种机制抑制乳腺癌和肺癌的生长，即抑制血管生成反应和抑制肿瘤细胞向肿瘤核心外的迁移。对ATE+31抑制迁移机制的研究表明，生长因子诱导的粘着斑激酶(FAK)磷酸化的增加可被ATE+31取消。磷酸化水平的降低发生在Tyr397、Tyr407和Tyr861。随之而来的是，暴露于ATE+31抑制了微丝的重组和伴随生长因子治疗的局灶性粘连的丧失，使得增强运动性很难实现。这个项目将解决的假设表明，ATE+31通过抑制增强的磷酸化而抑制FAK功能的机制来抑制细胞迁移。该项目将研究ATE-31抑制细胞迁移的机制，并使用动物模型在体内测试体外结果。具体地说，该项目将确定ATE+31抑制FAK磷酸化的机制，以及它如何随后抑制局灶性黏附/微丝动力学，并使用小鼠血管生成和肿瘤发展的模型来测试体内的实验结果。此外，ATE+31的治疗潜力将在肿瘤发展、消退和转移的动物模型中进行评估。