IGF‐independent effects of insulin‐like growth factor binding protein‐5 (Igfbp5) in vivo
| Autor: | Laura J. Cobb, Dervis A. Salih, Gyanendra Tripathi, Anja C. Drozd, Ruth A. Cosgrove, Jennifer M. Pell |
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| Rok vydání: | 2009 |
| Předmět: |
Genetically modified mouse
Transgene Mutant Gene Expression Mice Transgenic Biology Muscle Development Biochemistry Insulin-like growth factor-binding protein Mice Pregnancy Somatomedins Gene expression Genetics Animals Tissue Distribution RNA Messenger Muscle Skeletal Receptor Molecular Biology DNA Primers Mice Knockout Base Sequence Molecular biology Phenotype Mice Mutant Strains Recombinant Proteins Cell biology Mutation biology.protein Female Signal transduction Insulin-Like Growth Factor Binding Protein 5 hormones hormone substitutes and hormone antagonists Signal Transduction Biotechnology |
| Zdroj: | The FASEB Journal. 23:2616-2626 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.08-114124 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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