INHIBITION OF IGF MEDIATED TUMORIGENESIS

抑制 IGF 介导的肿瘤发生

• 批准号: 6633255
• 负责人: STEVEN Alan ROSENZWEIG
• 金额: $ 25.74万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633255
• 关键词: affinity labeling; binding proteins; binding sites; biotin; carcinogenesis inhibitor; chemical models; drug design /synthesis /production; growth factor receptors; insulinlike growth factor; intermolecular interaction; laboratory rabbit; mass spectrometry; molecular chaperones; molecular dynamics; peptide library; protein structure function; recombinant proteins; site directed mutagenesis; tissue /cell culture

The insulin-like growth factor 1 (IGF-1 receptor (IGF-1R) is an essential regulator of cell growth and transformation. IGF-1 and IGF-2, via the IGF-1R, are potent breast cancer cell mitogens that promote the tumorigenic potential of cancer cells. The objective of this proposal is to develop reagents that block IGF-1R signaling. The insulin-like growth factor binding proteins (IGFBPs) bind IGF-1 and IGF-2 with higher affinities than the IGF-1R and serve to both protect the IGFs from degradation and reduce their delivery to the IGF-1R. The hypothesis of the proposal is that blockade of IGF-1R activity can be accomplished by developing IGF antagonists based on the structure of the IGF binding domain on the IGFBPs. The goal of Aim 1 is to define the structure of the IGF-binding domain on rhIGFBP-2 using photoaffinity labeling and mass spectrometric analyses. To this end, IGF-1 derivatized with photactivatable groups within its IGFBP-binding domain will be synthesized. This will allow the precise identification of the sites of interaction between rhIGFBP-2 and IGF-1. Based on these analyses, deletion, truncation and site-directed mutants of IGFBP-2 will be generated and tested for IGF binding activity. Aim 2 will characterize the structure and function of a 15.8 kDa fragment of IGFBP-2. The goal of Aim 3 is to examine the mechanism responsible for IGFBPP-2 inhibition of IGF action. The goal of Aim 4 is to employ phage display to screen libraries for peptides having a high affinity for the IGFBP-binding domain on IGF-1 as an alternative means of designing IGF antagonists.

胰岛素样生长因子1（IGF-1受体（IGF-1R）是一种 细胞生长和转化的基本调节剂。 IGF-1和IGF-2，通过 IGF-1R是有效的乳腺癌细胞有丝分裂剂，可促进肿瘤性 癌细胞的潜力。该提议的目的是发展 阻断IGF-1R信号传导的试剂。胰岛素样生长因子结合 蛋白质（IGFBP）与IGF-1R相结合的IGF-1和IGF-2比IGF-1R更高 并有助于保护IGF免受降解并减少其交付 到IGF-1R。该提案的假设是IGF-1R的封锁 可以通过基于IGF拮抗剂来实现活动 IGFBPS上IGF结合域的结构。目标1的目标是 使用PhotoAdrotiention在RhigFBP-2上定义IGF结合域的结构 标记和质谱分析。为此，IGF-1衍生 将合成其IGFBP结合域中的光活化基团。 这将允许精确地识别 RHIGFBP-2和IGF-1。基于这些分析，删除，截断和 IGFBP-2的位置定向突变体将产生并测试IGF结合 活动。 AIM 2将表征15.8 kDa的结构和功能 IGFBP-2的片段。目标3的目标是检查负责的机制 用于IGFBPP-2抑制IGF作用。目标4的目标是使用噬菌体 显示到屏幕库，以使肽具有很高的亲和力 IGF-1上的IGFBP结合域，作为设计IGF的替代方法 对手。