Mechanisms of Modulation of IGF's Action

最近来自敲除或过表达小鼠的研究证据表明，胰岛素样生长因子（igf）和/或其受体对哺乳动物的正常发育和生长至关重要。此外，在许多细胞类型中，IGFs已被证明具有多种生物活性，包括诱导细胞增殖和分化、抑制细胞凋亡和维持细胞功能的能力。IGFs与几种特异性结合蛋白（igfbp）作为复合物在血浆和整个细胞外空间循环。目前认为igfbp控制IGFs的半衰期和调节IGFs的可用性；然而，它们的生理作用尚不清楚。尽管IGFs的生物活性丰富多样，但其体外生物学效应相对较弱，除非有其他激素或生长因子存在，否则往往无法证明。在此背景下，本研究旨在确定细胞外和细胞内调节IGFs生物活性的机制，以应对其他激素或生长因子，以及不同的生理条件。首先，在不同的生理条件下，我们分析了血清中IGF和igfbp的产生，IGF和igfbp的相互作用，IGF受体的表达。我们的研究结果表明，IGF/IGFBP/IGF受体的表达受到不同方式的调控，导致IGF在不同的生理情况下具有合理的生物活性。此外，在内分泌细胞中，我们证明了热带激素通过细胞内信号的串扰机制诱导细胞对IGF-I作出反应。在肝细胞中，观察到胰岛素和camp之间类似的增强，表明串扰机制对控制胰岛素样活性非常重要。从这些数据中，我们得出结论，IGF的生物活性受1)IGFs的产生，2)igfbp的产生，3)IGFs与igfbp的相互作用，4)IGF受体的表达，5)IGF信号转导的过程调节，以响应其他激素或生长因子以及生理条件。这种调节是哺乳动物正常发育和生长所必需的。少

Recent evidence, derived from studies using knock-out or overexpression mice, indicates that insulinlike growth factors (IGFs) and/or their receptors are essential for the normal development and growth of mammals. Further, in many cell types IGFs have been shown to possess a variety of bioactivities, including the ability to induce cell proliferation and differentiaton, to inhibit cell apoptosis, and to maintain cell functio. IGFs circulates in the plasma and throughout the extracellular space as a complex with several specific binding proteins (IGFBPs). IGFBPs are believed at present to control half-lives of IGFs and modulate IGFs availability ; however, their physiological roles are still unclear. Despite the profuseness and diversity of IGFs bioactivities, the in vitro biological effects of IGFs are relatively weak and often are not demonstrable except in the presence of other hormones or growth factors. From this background, this study was undertaken to determine extracellular and … More intracellular mechanisms to modulate IGFs bioactivities in response to other hormones or growth factors, and different physiological conditions. Firstly, under various physiological conditions, we analyzed production of IGFs and IGFBPs interaction between IGFs and IGFBPs in serum, expression of IGF receptors. Our results suggested that expression of IGF/IGFBP/IGF receptors is regulated in different manners, resulting in reasonable IGFs bioactivities in response to each physiological situation. In additions, in endocrine cells, we demonstrated that tropic hormones prime cells to respond to IGF-I through cross-talk mechanisms of the intracellular signals. In liver cells, the similar potentiation between insulin and camp was observed, suggesting that the cross-talk mechanisms are very important to control insulin-like activities in general. From a series of these data, we concluded that IGF bioactivities are modulated by the process of 1) IGFs production, 2) IGFBPs production, 3) interaction between IGFs and IGFBPs, 4) IGF receptor expression, and 5) IGF signal transduction, in response to other hormones or growth factors as well as physiological conditions. This modulation must be required for normal development and growth of mammals. Less