Overexpression of Gly56/Gly80/Gly81-Mutant Insulin-Like Growth Factor-Binding Protein-3 in Transgenic Mice
| Autor: | Liam J. Murphy, Suresh Mishra, Arnold Leckstrom, Josef V. Silha, Yaoting Gui, Pinchas Cohen |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Genetically modified mouse medicine.medical_specialty DNA Complementary Ratón Transgene Blotting Western Mutant Glycine Apoptosis Mice Transgenic Biology Ligands Insulin-like growth factor-binding protein Mice Ribonucleases Sex Factors Endocrinology Species Specificity In vivo Proliferating Cell Nuclear Antigen Internal medicine medicine Animals Humans Tissue Distribution Transgenes Insulin-Like Growth Factor I Chromatography Brain Organ Size Embryo Mammalian Immunohistochemistry Molecular biology In vitro Proliferating cell nuclear antigen Blotting Southern Insulin-Like Growth Factor Binding Protein 3 COS Cells Mutation Mutagenesis Site-Directed biology.protein RNA Female |
| Zdroj: | Endocrinology. 146:1523-1531 |
| ISSN: | 1945-7170 0013-7227 |
| Popis: | IGF-independent effects of IGF-binding protein-3 (IGFBP-3) have been demonstrated in vitro; however, the physiological significance of these effects in vivo is unclear. We generated two transgenic (Tg) mouse strains that overexpress a human Gly56/Gly80/Gly81-mutant IGFBP-3 cDNA. This mutant has a markedly reduced affinity for the IGFs, but retains the IGF-independent effects. Serum levels of mutant IGFBP-3 were 156 ± 12 and 400 ± 24 ng/ml in hemizygous mice of strains 5005 and 5012, respectively. When Tg and wild-type mice were compared, there was no reduction in birth weight, litter size, or postnatal growth. Despite differences in transgene expression in various tissues, relative organ weight was similar in Tg and wild-type mice, with exception of brain, where a modest reduction in brain weight was observed in the high-expressing 5012 lineage. There was also a significant reduction in proliferating cell nuclear antigen-staining cells observed in the periventricular region of the developing brain in embryonic d 18 Tg embryos. In the higher expressing 5012 Tg strain, IGF-I and murine IGFBP-3 levels, marker of GH action were increased. Furthermore, there was a positive correlation between mutant IGFBP-3 levels and IGF-I levels and between mutant IGFBP-3 levels and murine IGFBP-3 (P = 0.002 and P < 0.001, respectively). These data indicate that overexpression of mutant IGFBP-3 is not associated with growth retardation. The higher levels of IGF-I and murine IGFBP-3 in the 5012 Tg strain suggest that the growth inhibitory effect of mutant IGFBP-3 may be compensated for by other mechanisms. |
| Databáze: | OpenAIRE |
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