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Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant.
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| Zeitschriftentitel: | Proceedings of the National Academy of Sciences |
|---|---|
| Personen und Körperschaften: | , , , |
| In: | Proceedings of the National Academy of Sciences, 91, 1994, 6, S. 2181-2185 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Proceedings of the National Academy of Sciences
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| Schlagwörter: |
| author_facet |
Prager, D Li, H L Asa, S Melmed, S Prager, D Li, H L Asa, S Melmed, S |
|---|---|
| author |
Prager, D Li, H L Asa, S Melmed, S |
| spellingShingle |
Prager, D Li, H L Asa, S Melmed, S Proceedings of the National Academy of Sciences Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. Multidisciplinary |
| author_sort |
prager, d |
| spelling |
Prager, D Li, H L Asa, S Melmed, S 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.91.6.2181 <jats:p>Although insulin-like growth factor I (IGF-I) is a mitogenic growth factor, its role in tumorigenesis is unclear. We therefore transfected wild-type and truncated beta-subunit mutant (952STOP) human IGF-I receptor cDNAs into Rat-1 fibroblasts. Rat-1 transfectants expressed 2.5- to 7-fold increased IGF-I receptor mass, while the Kd for IGF-I binding was unchanged. The Rat-1 cells transfected with wild-type receptor cDNA responded to in vitro IGF-I treatment by increased proliferation and DNA synthesis. Cells overexpressing wild-type receptors were also transformed as evidenced by ligand-dependent colony proliferation in soft agar. After injection into athymic nude mice, all wild-type transfectants formed solid sarcomas within 3 weeks, and ex vivo tumor cell assays confirmed continued overexpression of human IGF-I receptors. In contrast, both DNA synthesis and proliferation of 952STOP-transfected cells were attenuated below that of untransfected cells. 952STOP cells were nonresponsive to IGF-I in vitro and were unable to sustain anchorage-independent growth. No tumors were induced for up to 8 weeks after injection of 952STOP transfectants into athymic mice, despite the presence of demonstrable endogenous IGF-I receptors on the 952STOP-transfected cells. Therefore, 952STOP behaves as a dominant negative inhibitor of endogenous IGF-I receptor function, probably by assembling nonfunctional hybrid rat/mutant human receptor tetramers.</jats:p> Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. Proceedings of the National Academy of Sciences |
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| title |
Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_unstemmed |
Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_full |
Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_fullStr |
Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_full_unstemmed |
Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_short |
Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_sort |
dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor i receptor mutant. |
| topic |
Multidisciplinary |
| url |
http://dx.doi.org/10.1073/pnas.91.6.2181 |
| publishDate |
1994 |
| physical |
2181-2185 |
| description |
<jats:p>Although insulin-like growth factor I (IGF-I) is a mitogenic growth factor, its role in tumorigenesis is unclear. We therefore transfected wild-type and truncated beta-subunit mutant (952STOP) human IGF-I receptor cDNAs into Rat-1 fibroblasts. Rat-1 transfectants expressed 2.5- to 7-fold increased IGF-I receptor mass, while the Kd for IGF-I binding was unchanged. The Rat-1 cells transfected with wild-type receptor cDNA responded to in vitro IGF-I treatment by increased proliferation and DNA synthesis. Cells overexpressing wild-type receptors were also transformed as evidenced by ligand-dependent colony proliferation in soft agar. After injection into athymic nude mice, all wild-type transfectants formed solid sarcomas within 3 weeks, and ex vivo tumor cell assays confirmed continued overexpression of human IGF-I receptors. In contrast, both DNA synthesis and proliferation of 952STOP-transfected cells were attenuated below that of untransfected cells. 952STOP cells were nonresponsive to IGF-I in vitro and were unable to sustain anchorage-independent growth. No tumors were induced for up to 8 weeks after injection of 952STOP transfectants into athymic mice, despite the presence of demonstrable endogenous IGF-I receptors on the 952STOP-transfected cells. Therefore, 952STOP behaves as a dominant negative inhibitor of endogenous IGF-I receptor function, probably by assembling nonfunctional hybrid rat/mutant human receptor tetramers.</jats:p> |
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| author | Prager, D, Li, H L, Asa, S, Melmed, S |
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| description | <jats:p>Although insulin-like growth factor I (IGF-I) is a mitogenic growth factor, its role in tumorigenesis is unclear. We therefore transfected wild-type and truncated beta-subunit mutant (952STOP) human IGF-I receptor cDNAs into Rat-1 fibroblasts. Rat-1 transfectants expressed 2.5- to 7-fold increased IGF-I receptor mass, while the Kd for IGF-I binding was unchanged. The Rat-1 cells transfected with wild-type receptor cDNA responded to in vitro IGF-I treatment by increased proliferation and DNA synthesis. Cells overexpressing wild-type receptors were also transformed as evidenced by ligand-dependent colony proliferation in soft agar. After injection into athymic nude mice, all wild-type transfectants formed solid sarcomas within 3 weeks, and ex vivo tumor cell assays confirmed continued overexpression of human IGF-I receptors. In contrast, both DNA synthesis and proliferation of 952STOP-transfected cells were attenuated below that of untransfected cells. 952STOP cells were nonresponsive to IGF-I in vitro and were unable to sustain anchorage-independent growth. No tumors were induced for up to 8 weeks after injection of 952STOP transfectants into athymic mice, despite the presence of demonstrable endogenous IGF-I receptors on the 952STOP-transfected cells. Therefore, 952STOP behaves as a dominant negative inhibitor of endogenous IGF-I receptor function, probably by assembling nonfunctional hybrid rat/mutant human receptor tetramers.</jats:p> |
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| imprint | Proceedings of the National Academy of Sciences, 1994 |
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| spelling | Prager, D Li, H L Asa, S Melmed, S 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.91.6.2181 <jats:p>Although insulin-like growth factor I (IGF-I) is a mitogenic growth factor, its role in tumorigenesis is unclear. We therefore transfected wild-type and truncated beta-subunit mutant (952STOP) human IGF-I receptor cDNAs into Rat-1 fibroblasts. Rat-1 transfectants expressed 2.5- to 7-fold increased IGF-I receptor mass, while the Kd for IGF-I binding was unchanged. The Rat-1 cells transfected with wild-type receptor cDNA responded to in vitro IGF-I treatment by increased proliferation and DNA synthesis. Cells overexpressing wild-type receptors were also transformed as evidenced by ligand-dependent colony proliferation in soft agar. After injection into athymic nude mice, all wild-type transfectants formed solid sarcomas within 3 weeks, and ex vivo tumor cell assays confirmed continued overexpression of human IGF-I receptors. In contrast, both DNA synthesis and proliferation of 952STOP-transfected cells were attenuated below that of untransfected cells. 952STOP cells were nonresponsive to IGF-I in vitro and were unable to sustain anchorage-independent growth. No tumors were induced for up to 8 weeks after injection of 952STOP transfectants into athymic mice, despite the presence of demonstrable endogenous IGF-I receptors on the 952STOP-transfected cells. Therefore, 952STOP behaves as a dominant negative inhibitor of endogenous IGF-I receptor function, probably by assembling nonfunctional hybrid rat/mutant human receptor tetramers.</jats:p> Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. Proceedings of the National Academy of Sciences |
| spellingShingle | Prager, D, Li, H L, Asa, S, Melmed, S, Proceedings of the National Academy of Sciences, Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant., Multidisciplinary |
| title | Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_full | Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_fullStr | Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_full_unstemmed | Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_short | Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| title_sort | dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor i receptor mutant. |
| title_unstemmed | Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. |
| topic | Multidisciplinary |
| url | http://dx.doi.org/10.1073/pnas.91.6.2181 |