Tripathi Gyanendra, Salih Dervis A M, Drozd Anja C, Cosgrove Ruth A, Cobb Laura J, Pell Jennifer M
Laboratory of Molecular Signalling, The Babraham Institute, Cambridge CB22 3AT, UK.
FASEB J. 2009 Aug;23(8):2616-26. doi: 10.1096/fj.08-114124. Epub 2009 Mar 30.
IGF activity is regulated tightly by a family of IGF binding proteins (IGFBPs). IGFBP-5 is the most conserved of these and is up-regulated significantly during differentiation of several key lineages and in some cancers. The function of IGFBP-5 in these physiological and pathological situations is unclear, however, several IGFBP-5 sequence motifs and studies in vitro suggest IGF-independent actions. Therefore, we aimed to compare the phenotypes of mice overexpressing wild-type Igfbp5 or an N-terminal mutant Igfbp5 with negligible IGF binding affinity. Both significantly inhibited growth, even at low expression levels. Even though wild-type IGFBP-5 severely disrupted the IGF axis, we found no evidence for interaction of mutant IGFBP-5 with the IGF system. Further, overexpression of wild-type IGFBP-5 rescued the lethal phenotype induced by "excess" IGF-II in type 2 receptor-null mice; mutant IGFBP-5 overexpression could not. Therefore, wild-type IGFBP-5 provides a very effective mechanism for the inhibition of IGF activity and a powerful in vivo mechanism to inhibit IGF activity in pathologies such as cancer. This study is also the first to suggest significant IGF-independent actions for IGFBP-5 during development.
胰岛素样生长因子（IGF）的活性受到一类IGF结合蛋白（IGFBPs）的严格调控。IGFBP - 5是其中最保守的一种，在几个关键谱系的分化过程以及某些癌症中显著上调。然而，IGFBP - 5在这些生理和病理情况下的功能尚不清楚，不过，一些IGFBP - 5序列基序以及体外研究表明其存在不依赖IGF的作用。因此，我们旨在比较过表达野生型Igfbp5或N端突变型Igfbp5（其IGF结合亲和力可忽略不计）的小鼠的表型。即使在低表达水平时，两者均显著抑制生长。尽管野生型IGFBP - 5严重破坏了IGF轴，但我们未发现突变型IGFBP - 5与IGF系统相互作用的证据。此外，野生型IGFBP - 5的过表达挽救了2型受体缺失小鼠中由“过量”IGF - II诱导的致死表型；突变型IGFBP - 5的过表达则不能。因此，野生型IGFBP - 5提供了一种非常有效的抑制IGF活性的机制，以及一种在癌症等病理状态下抑制IGF活性的强大体内机制。本研究也是首次表明IGFBP - 5在发育过程中存在显著的不依赖IGF的作用。
