IGF-independent effects of insulin-like growth factor binding protein-5 (Igfbp5) in vivo
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 u...
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| Veröffentlicht in: | The FASEB journal 2009-08, Vol.23 (8), p.2616-2626 |
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| creator | Tripathi, Gyanendra Salih, Dervis A.M Drozd, Anja C Cosgrove, Ruth A Cobb, Laura J Pell, Jennifer M |
| description | 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.--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. |
| doi_str_mv | 10.1096/fj.08-114124 |
| format | Article |
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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.--Tripathi, G., Salih, D. A. M., Drozd, A. C., Cosgrove, R. A., Cobb, L. J., Pell, J. M. 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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.--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.</description><subject>Animals</subject><subject>Base Sequence</subject><subject>DNA Primers - genetics</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Insulin-Like Growth Factor Binding Protein 5 - deficiency</subject><subject>Insulin-Like Growth Factor Binding Protein 5 - genetics</subject><subject>Insulin-Like Growth Factor Binding Protein 5 - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mice, Mutant Strains</subject><subject>Mice, Transgenic</subject><subject>muscle</subject><subject>Muscle Development</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Mutation</subject><subject>Phenotype</subject><subject>Pregnancy</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal Transduction</subject><subject>Somatomedins - metabolism</subject><subject>Tissue Distribution</subject><subject>transgenic</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1PGzEQhq2KqgTaW8_FpwqkLvgjdrzHEhEahNQDReJmee2Z4LDZXdYbIv59jTZqb1w8l-d9NH6HkK-cnXNW6gtcnzNTcD7lYvqBTLiSrNBGswMyYaYUhdbSHJKjlNaMMc64_kQOeSml0FMzIQ_L60URmwAd5KcZKCCCHxJtkcYmbevYFHV8Arrq293wSNH5oe1plSOxWdGubwfIiKKnyxVWnTrLKfoSX9rP5CO6OsGX_Twm94urP_Nfxe3v6-X8523hZSmnhXDgUCmJM3TGiQBBlyE4BTIIA96grFCBMMJD_ozBoIXXASomSkBfCXlMvo_evMrzFtJgNzF5qGvXQLtNVs-UNGomM_hjBH3fptQD2q6PG9e_Ws7sW5MW15YZOzaZ8W9777baQPgP76vLgBmBXazh9V2ZXdxdisUNM__cJ2MUXWvdqo_J3t8JxmW-juZSGvkXYhaJHQ</recordid><startdate>200908</startdate><enddate>200908</enddate><creator>Tripathi, Gyanendra</creator><creator>Salih, Dervis A.M</creator><creator>Drozd, Anja C</creator><creator>Cosgrove, Ruth A</creator><creator>Cobb, Laura J</creator><creator>Pell, Jennifer M</creator><general>The Federation of American Societies for Experimental Biology</general><general>Federation of American Societies for Experimental Biology</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200908</creationdate><title>IGF-independent effects of insulin-like growth factor binding protein-5 (Igfbp5) in vivo</title><author>Tripathi, Gyanendra ; 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| subjects | Animals Base Sequence DNA Primers - genetics Female Gene Expression Insulin-Like Growth Factor Binding Protein 5 - deficiency Insulin-Like Growth Factor Binding Protein 5 - genetics Insulin-Like Growth Factor Binding Protein 5 - metabolism Mice Mice, Knockout Mice, Mutant Strains Mice, Transgenic muscle Muscle Development Muscle, Skeletal - metabolism Mutation Phenotype Pregnancy Recombinant Proteins - genetics Recombinant Proteins - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism Signal Transduction Somatomedins - metabolism Tissue Distribution transgenic |
| title | IGF-independent effects of insulin-like growth factor binding protein-5 (Igfbp5) in vivo |
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