Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice
Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice
复制标题
DOI：
10.1210/en.142.5.1958
复制
发表时间：
2001-05-01
期刊：
影响因子：
4.8
通讯作者：
Murphy, LJ
中科院分区：
文献类型：
--
作者：
Modric, T;Silha, JV;Murphy, LJ
在细胞培养系统中，胰岛素样生长因子结合蛋白-3(IGFBP-3)既可以增强IGF-T的作用，也可以抑制IGF-T的作用。为了探讨IGFBP-3在体内的生物学作用，对由小鼠磷酸甘油酸激酶I(PGK)和巨细胞病毒(CMV)启动子驱动的人IGFBP-3互补DNA(CDNAs)过表达的转基因(TG)小鼠进行了检测。CMVBP-3和PGKBP-S转基因小鼠血清中人IGFBP3水平分别为4.7和5.8ug/ml，总IGFBP3水平分别是野生型(Wt)小鼠的4.9倍和7.7倍。在PGKBP-8TG小鼠中，转基因在所有组织中的表达水平都是相似的。尽管CMVBP-3小鼠在大多数组织中表现出与PGKBP-3小鼠相似的转基因表达水平，但在肾脏和心脏中的表达明显增强。转基因IGFBP-3以150 KDa的三元复合体形式循环，与Wt小鼠相比，Tg小鼠的血清IGF-I水平提高了1.9-2.8倍，出生体重显著减少约10%，产仔数也略有减少。与Wt鼠相比，Tg鼠的早期出生后生长(通过体重和身长来评估)显著降低。这在PGKBP-8小鼠中比在CMVBP-3小鼠中更明显，后者在断奶后表现出肥胖的倾向。两种品系的小鼠脑和肾的相对脏器重量均明显减轻，而肝脏大小和附睾脂含量在CMVBP-3组显著增加，而PGKBP-8组无明显变化。我们的数据表明，尽管循环中IGF-I水平升高，IGFBP-3的过度表达与轻度宫内和出生后发育迟缓有关。
In cell culture systems insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) can both enhance and inhibit IGF-T action. To investigate the biological role of IGFBP-3 in vivo, transgenic (Tg) mice that constitutively overexpress the human IGFBP-3 complementary DNA (cDNA) driven by the mouse phosphoglycerate kinase I(PGK) and the cytomegalovirus (CMV) promoters were examined. Serum levels of human IGFBP-3 in CMVBP-3 and PGKBP-S Tg mice were 4.7 and 5.8 mug/ml, respectively and total IGFBP-3 was increased 4.9- and 7.7-fold compared with that in wild-type (Wt) mice. In PGKBP-8 Tg mice the levels of transgene expression were similar in all tissues. Although CMVBP-3 mice demonstrated similar levels of expression of the transgene as PGKBP-3 mice in most tissues, markedly elevated expression was apparent in the kidney and heart. The transgene- derived IGFBP-3 circulated as a 150-KDa ternary complex, and serum IGF-I levels were elevated 1.9- to 2.8-fold in Tg mice compared with Wt mice, A significant reduction in birth weight of approximately 10% and a modest-reduction in litter size were apparent in both Tg strains. Early postnatal growth, as assessed by both body weight and length, was significantly reduced in Tg mice compared with Wt mice. This was more marked in PGKBP-8 than in CMVBP-3 mice, who demonstrated a propensity to adiposity after weaning. The relative organ weights of brain and kidney were reduced in both Tg strains, whereas liver size and epididymal fat were significantly increased in CMVBP-3, but not PGKBP-8, mice. Our data indicate that overexpression of IGFBP-3 is associated with modest intrauterine and postnatal growth retardation despite elevated circulating IGF-I levels.