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IGF‐independent effects of insulin‐like growth factor binding protein‐5 ( Igfbp5) in vivo
Author(s) -
Tripathi Gyanendra,
Salih Dervis A. M.,
Drozd Anja C.,
Cosgrove Ruth A.,
Cobb Laura J.,
Pell Jennifer M.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-114124
Subject(s) - insulin like growth factor binding protein , mutant , in vivo , phenotype , growth factor , biology , insulin like growth factor , wild type , receptor , insulin like growth factor receptor , in vitro , endocrinology , microbiology and biotechnology , cancer research , medicine , gene , genetics
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 . FASEBJ. 23, 2616–2626 (2009)