BIOLOGICAL ACTIONS OF IGFBP-3 FRAGMENTS

IGFBP-3 片段的生物学作用

• 批准号: 6164539
• 负责人: RON G ROSENFELD
• 金额: $ 19.59万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164539
• 关键词: Baculoviridae; binding proteins; binding sites; cell growth regulation; chemical cleavage; endopeptidases; gene expression; insulinlike growth factor

The insulin-like growth factors (IGFs) are fundamental mitogenic and differentiative polypeptides which exert their effects through specific IGF receptors. In the circulation, IGFs are bound to IGF binding proteins (IGFBPs). The predominant IGFP is IGFBP-3, which regulates IGF hormonal action by serving as a transport protein within the extracellular and vascular spaces, extending the half life of IGF, sequestering IGF and inhibiting the interaction of IGF peptides with their receptors. More recently, IGFBP-3 has been shown in our laboratory to act independently of IGF, through a specific IGFBP-3 binding site, thereby potently inhibiting cell replication. An additional complexity of the regulation of IGF by IGFBP-3 is the recent discovery by our group and others of IGFBP-3 protease(s), which have been detected in numerous biological fluids, where they degrade IGFBP-3 into fragments with reduced affinity for IGF. This modifies the interaction between IGFs and IGFBPs, and alters the bioavailability of IGF peptides for receptors, and the subsequent biological activity and function of IGF. Preliminary data have shown a proteolysed IGFBP-3 fragment to inhibit cell growth, independent of its ability to bind IGF. However, the physiological implications of IGFBP-3 proteolysis have not been fully examined. The IGFBP-3 fragments have been neither fully purified nor characterized, nor has the physiological important of these IGFBP-3 forms been critically examined, either as IGF inhibitors, IGF potentiators, or IGF-independent growth regulators. Thus, the central hypothesis of this proposal is: PROTEOLYSIS OF IGFBP-3 MODIFIES ITS BIOLOGICAL ACTIVITY AND HORMONAL ACTION. We propose to: 1) determine the primary protease-dependent cleavage site(s) of IGFBP-3; 2) express IGFBP-3 and IGFBP-3 proteolytic fragments in a Baculovirus expression system; 3) characterize the IGFBP-3 fragments as IGF inhibitors or potentiators and as IGF-independent regulators of cell growth.

胰岛素样生长因子（IGF）是基本的促有丝分裂因子， 这些多肽通过特异性的 IGF受体。在循环中，IGF与IGF结合蛋白结合 （IGFBPs）。主要的IGFP是IGFBP-3，其调节IGF激素 作为细胞外的转运蛋白， 血管空间，延长IGF的半衰期，隔离IGF， 抑制IGF肽与其受体的相互作用。更 最近，IGFBP-3已在我们的实验室中显示出独立于 IGF通过特异性IGFBP-3结合位点，从而有效抑制 细胞复制 IGFBP-3调节IGF的另一个复杂性是最近的 我们的小组和其他人发现了IGFBP-3蛋白酶， 在许多生物液体中检测到，它们将IGFBP-3降解为 对IGF亲和力降低的片段。这会修改交互 IGFs和IGFBPs之间，并改变IGF肽的生物利用度 受体，以及随后的生物活性和IGF的功能。 初步数据显示，蛋白水解的IGFBP-3片段抑制细胞增殖， 生长，独立于其结合IGF的能力。然而，生理 IGFBP-3蛋白水解的影响尚未得到充分研究。的 IGFBP-3片段既没有完全纯化，也没有表征， 这些IGFBP-3形式的生理重要性是否已经被严格地 检查，无论是作为IGF抑制剂，IGF增效剂，或IGF独立 生长调节剂。因此，这一建议的核心假设是： IGFBP-3的蛋白水解改变其生物活性和激素 行动上 我们建议：1）确定初级蛋白酶依赖的切割 IGFBP-3位点; 2）表达IGFBP-3和IGFBP-3蛋白水解片段 杆状病毒表达系统; 3）表征IGFBP-3片段 作为IGF抑制剂或增强剂和作为IGF非依赖性调节剂， 细胞生长

项目成果

Connective tissue growth factor (IGFBP-rP2) expression and regulation in cultured bovine endothelial cells.

• DOI: 10.1210/endo.140.4.6633
• 发表时间: 1999-04
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Mary Boes;Mary Boes;B. Dake;B. Dake;Barbara A. Booth;Barbara A. Booth;N. Erondu;N. Erondu