BIOLOGICAL ACTIONS OF IGFBP-3 FRAGMENTS

IGFBP-3 片段的生物学作用

• 批准号: 2882790
• 负责人: RON G ROSENFELD
• 金额: $ 19.2万
• 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/2882790
• 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（IGFs）是基本的有丝分裂和