NEGATIVE REGULATION OF IGF-11 BY THE IGF-11R IN CANCER

IGF-11R 在癌症中对 IGF-11 的负调节

• 批准号: 6150198
• 负责人: MATTHEW J ELLIS
• 金额: $ 5.84万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-15 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150198
• 关键词: MCF7 cell; apoptosis; athymic mouse; biological signal transduction; cell cycle; enzyme activity; growth factor receptors; hormone regulation /control mechanism; inhibitor /antagonist; insulinlike growth factor; ligands; lysosomes; mannose 6 phosphate; molecular site; mutant; neoplastic cell; neoplastic transformation; protein tyrosine kinase; receptor binding; receptor expression; receptor mediated endocytosis; transfection /expression vector; transport proteins; tumor suppressor genes

Insulin-like growth factor II plays a prominent role in malignant transformation by activating the IGF-I receptor. Activated IGF-IR promotes malignant growth by stimulating cellular proliferation and by inhibiting apoptosis. IGF-II also binds to the mannose 6-phosphate/IGF-II receptor (IGF-IIR), a transport molecule controlling IGF-II availability during embryogenesis. We hypothesize that the IGF-IIR also limits IGF-II signalling in malignant cells. In an autocrine model of IGF-II signalling, we demonstrated that IGF-IIR inhibited the extracellular accumulation of IGF-II, thereby reducing IGF-IR-dependent cellular proliferation and anchorage-independent growth. These observations lead us to propose the following research aims: l) To confirm that the IGF-IIR acts as an IGF-II antagonist by overexpressing the IGF-IIR with a panel of mutant IGF mutant peptides with altered receptor affinity. We anticipate that IGF-IIR overexpression, only when coexpressed with high IGF-IIR avidity ligands, will repress extracellular IGF availability; 2) IGF-IIR overexpression, suppressing IGF-II signalling, may provide a mechanism to reverse or inhibit IGF-II-dependent malignancy. We will test this hypothesis in IGF-II expressing sarcoma cell lines, 3) The third aim will further explore the antagonistic actions of IGF-IIR, employing receptor mutants with altered ligand binding and transport properties. Given that autocrine IGF-II expression is a prominent feature of sarcomas, for which treatment options are limited, investigation of a novel mechanism of growth factor suppression serves the long term goal of designing new therapeutic approaches.

胰岛素样生长因子II在恶性肿瘤中发挥着重要作用 通过激活 IGF-I 受体进行转化。激活的 IGF-IR 促进 通过刺激细胞增殖和抑制恶性生长 细胞凋亡。 IGF-II 还与 6-磷酸甘露糖/IGF-II 受体结合 (IGF-IIR)，一种控制 IGF-II 可用性的运输分子 胚胎发生。我们假设 IGF-IIR 也限制 IGF-II 恶性细胞中的信号传导。在 IGF-II 信号传导的自分泌模型中， 我们证明 IGF-IIR 抑制细胞外积累 IGF-II，从而减少 IGF-IR 依赖性细胞增殖和 不依赖锚定的生长。 这些观察结果使我们提出以下研究目标： l) 通过过度表达确认 IGF-IIR 作为 IGF-II 拮抗剂 IGF-IIR 与一组突变 IGF 突变肽 受体亲和力。我们预计 IGF-IIR 过度表达，仅当 与高 IGF-IIR 亲合力配体共表达，将抑制细胞外 IGF 可用性； 2) IGF-IIR过度表达，抑制IGF-II 信号传导，可能提供逆转或抑制 IGF-II 依赖性的机制 恶性肿瘤。我们将在表达 IGF-II 的肉瘤细胞中检验这一假设 线，3）第三个目标将进一步探讨 IGF-IIR，采用配体结合改变的受体突变体和 运输属性。 鉴于自分泌 IGF-II 表达是肉瘤的一个显着特征， 对于治疗选择有限的情况，研究一种新颖的 生长因子抑制机制服务于长期目标 设计新的治疗方法。