| Comparison of intracellular signalling by insulin and the hypermitogenic AspB10 analogue in MCF-7 breast adenocarcinoma cells. | |
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MedLine Citation:
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PMID: 20936651 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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We compared mitogenicity and intracellular signalling by human insulin and the AspB10 (X-10) human insulin analogue in MCF-7 human mammary adenocarcinoma cells. By flow analysis of phosphorylated histone H3 or cell cycle distributions, insulin and X-10 were mitogenic at physiologically relevant concentrations (2 nm to 74 pm range), with X-10 being approximately 3-fold more mitogenic than insulin. By western blotting with phospho-specific antibodies, insulin induced phosphorylation of IRS-1, Akt, p70S6K, S6 ribosomal protein, 4E-BP1, FoxO3a, FoxO1, p44/42 MAPK and the EGFR. Blocking with wortmannin, rapamycin and U0126 showed that these signalling events conformed to the canonical PI3K pathway. IRS-1 (Ser302) phosphorylation was abolished by wortmannin and rapamycin, suggesting a feedback from the PI3K pathway on insulin signalling. Compared with equimolar insulin, X-10 caused up to 2-fold higher phosphorylation of all proteins examined in this study. The phosphorylation sites that responded most strongly to insulin were not generally the same as those responding most strongly to X-10. In the PI3K pathway, the most X-10-sensitive protein localized to the translation-regulating arm (p70S6K), with FoxO3a and FoxO1 transcription factors showing a more comparable response to insulin and X-10. Using flow analysis, we confirmed the correlation between insulin-triggered translational activation in G0/G1 (S6 phosphorylation) and S-phase entry by MCF-7 cells. In summary, our findings implicate asymmetrical PI3K pathway activation and specifically stimulation of protein translation in the hypermitogenic effect of insulin analogues such as X-10. It remains to be shown whether these findings are relevant to other human mammary cancer cell types. Copyright © 2010 John Wiley & Sons, Ltd. |
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Authors:
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Martin B Oleksiewicz; Christine Bonnesen; Anne Charlotte Hegelund; Anders Lundby; Gitte-Mai Nelander Holm; Marianne B Jensen; Jonas S Krabbe |
Publication Detail:
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Type: Journal Article Date: 2010-10-08 |
Journal Detail:
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Title: Journal of applied toxicology : JAT Volume: 31 ISSN: 1099-1263 ISO Abbreviation: J Appl Toxicol Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-05-27 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8109495 Medline TA: J Appl Toxicol Country: England |
Other Details:
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Languages: eng Pagination: 329-41 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 John Wiley & Sons, Ltd. |
Affiliation:
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Molecular Toxicology, Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Maalov, Denmark. mboleks@gmail.com. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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