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https://hdl.handle.net/2440/61263
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dc.contributor.author | Brierley, G. | - |
dc.contributor.author | Macaulay, S. | - |
dc.contributor.author | Forbes, B. | - |
dc.contributor.author | Wallace, J. | - |
dc.contributor.author | Cosgrove, L. | - |
dc.contributor.author | Macaulay, V. | - |
dc.date.issued | 2010 | - |
dc.identifier.citation | Endocrinology, 2010; 151(4):1418-1427 | - |
dc.identifier.issn | 0013-7227 | - |
dc.identifier.issn | 0013-7227 | - |
dc.identifier.uri | http://hdl.handle.net/2440/61263 | - |
dc.description.abstract | Insulin receptor (IR) overexpression is common in cancers, with expression of the A isoform (IR-A, exon 11–) predominating over the B isoform. The IR-A signals a proliferative, antiapoptotic response to IGF-II, which itself can be secreted by tumors to establish an autocrine proliferative loop. Therefore, IGF-II signaling via the IR-A could mediate resistance to type 1 IGF receptor (IGF-IR) inhibitory drugs that are currently in development. This study addressed the role of the IR-A, using a small interfering RNA-based approach in SW480 human colon adenocarcinoma cells that coexpress the IGF-IR. Clonogenic survival was inhibited by depletion of the IGF-IR but not the IR-A, and dual receptor depletion had no greater effect than IGF-IR knockdown alone, suggesting that the IR-A could not compensate for IGF-IR loss. IGF-IR knockdown also resulted in a decrease in viability, whereas IR-A depletion resulted in increased viability. Consistent with this, upon IR-A depletion, we found a concomitant enhancement of IGF-IR activation by IGF-I and IGF-II, reduced formation of IGF-IR:IR-A hybrid receptors and increased IGF-IR homodimer formation. Together, these results suggest that IGF bioactivity is mediated more effectively by the IGF-IR than by the IR-A or receptor hybrids and that signaling via the IGF-IR is dominant to the IR-A in colon cancer cells that express both receptors. | - |
dc.description.statementofresponsibility | G.V. Brierley, S.L. Macaulay, B.E. Forbes, J.C. Wallace, L.J. Cosgrove and V.M. Macaulay | - |
dc.language.iso | en | - |
dc.publisher | Endocrine Soc | - |
dc.rights | Copyright © 2010 by The Endocrine Society | - |
dc.source.uri | http://dx.doi.org/10.1210/en.2009-1006 | - |
dc.subject | Cells, Cultured | - |
dc.subject | Cell Line | - |
dc.subject | Humans | - |
dc.subject | Indans | - |
dc.subject | Insulin | - |
dc.subject | Receptor, IGF Type 1 | - |
dc.subject | Receptor, Insulin | - |
dc.subject | Insulin-Like Growth Factor I | - |
dc.subject | Insulin-Like Growth Factor II | - |
dc.subject | Protein Isoforms | - |
dc.subject | RNA, Small Interfering | - |
dc.subject | Blotting, Western | - |
dc.subject | Flow Cytometry | - |
dc.subject | Transfection | - |
dc.subject | Reverse Transcriptase Polymerase Chain Reaction | - |
dc.subject | Immunoprecipitation | - |
dc.subject | Cell Survival | - |
dc.subject | Gene Silencing | - |
dc.subject | Dose-Response Relationship, Drug | - |
dc.subject | Protein Multimerization | - |
dc.title | Silencing of the insulin receptor isoform A favors formation of type 1 insulin-like growth factor receptor (IGF-IR) homodimers and enhances ligand-induced IGF-IR activation and viability of human colon carcinoma cells | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1210/en.2009-1006 | - |
pubs.publication-status | Published | - |
Appears in Collections: | Aurora harvest 5 Molecular and Biomedical Science publications |
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