IGF-independent effects of insulin-like growth factor binding protein-5 (Igfbp5) in vivo
IGF-independent effects of insulin-like growth factor binding protein-5 (Igfbp5) in vivo
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DOI：
10.1096/fj.08-114124
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发表时间：
2009-08-01
期刊：
影响因子：
4.8
通讯作者：
Pell, Jennifer M.
中科院分区：
文献类型：
--
作者：
Tripathi, Gyanendra;Salih, Dervis A. M.;Pell, Jennifer M.
胰岛素样生长因子的活性受胰岛素样生长因子结合蛋白家族(IGFBPs)的严格调控。IGFBP-5是其中最保守的，在几个关键谱系的分化过程中以及在一些癌症中显著上调。IGFBP-5在这些生理和病理情况下的功能尚不清楚，然而，一些IGFBP-5序列基序和体外研究表明，IGFBP-5的作用不依赖于IGF。因此，我们的目的是比较过度表达野生型Igfbp5的小鼠和N端具有可忽略的IGF结合亲和力的突变体Igfbp5的表型。两者都显著抑制生长，即使在低表达水平也是如此。尽管野生型IGFBP-5严重干扰了IGF轴，但我们没有发现突变的IGFBP-5与IGF系统相互作用的证据。此外，野生型IGFBP-5的过度表达挽救了由2型受体缺失小鼠中“过量”的IGF-II诱导的致命表型；突变型IGFBP-5的过度表达不能。因此，野生型IGFBP-5为抑制IGF活性提供了一个非常有效的机制，并为癌症等病理过程中抑制IGF活性提供了一个强大的体内机制。这项研究还首次表明IGFBP-5在发育过程中具有显著的IGF非依赖性作用。-Tripari，G.，Salih，D.A.M.，Drozd，A.C.，Cosgrove，R.A.，Cobb，L.J.，Pell，J.M.体内胰岛素样生长因子结合蛋白-5(Igfbp5)的IGF非依赖性作用。FASE B J.23,2616-2626(2009)
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 wildtype IGFBP-5 rescued the lethal phenotype induced by "excess" IGF-II in type 2 receptor-null mice; mutant IGFBP-5 overexpression could not. Therefore, wildtype 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.-Tripathi, G., Salih, D. A. M., Drozd, A. C., Cosgrove, R. A., Cobb, L. J., Pell, J. M. IGF-independent effects of insulin-like growth factor binding protein-5 ( Igfbp5) in vivo. FASEB J. 23, 2616-2626 ( 2009)