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| Content Provider | Springer Nature Link |
|---|---|
| Author | Bonnesen, Christine Nelander, Gitte Mai Hansen, Bo Falck Jensen, Pia Krabbe, Jonas S. Jensen, Marianne B. Hegelund, Anne Charlotte Svendsen, Jette E. Oleksiewicz, Martin B. |
| Copyright Year | 2009 |
| Abstract | Evaluating mitogenic signaling specifically through the human insulin receptor (IR) is relevant for the preclinical safety assessment of developmental insulin analogs. It is known that overexpression of IR sensitizes cells to the mitogenic effects of insulin, but it is essentially unknown how mitogenic responses can be optimized to allow practical use of such recombinant cell lines for preclinical safety testing. We constitutively overexpressed the short isoform of the human insulin receptor (hIR-A, exon 11-negative) in L6 rat skeletal myoblasts. Because the mitogenic effect of growth factors such as insulin is expected to act in G0/G1, promoting S-phase entry, we developed a combined topoinhibition + serum deprivation strategy to explore the effect of G0/G1 synchronization as an independent parameter in the context of serum deprivation, the latter being routinely used to reduce background in mitogenicity assays. G0/G1 synchronization significantly improved the mitogenic responses of L6-hIR cells to insulin, measured by 3H-thymidine incorporation. Comparison with the parental L6 cells using phospho-mitogen-activated protein kinase, phospho-AKT, as well as 3H-thymidine incorporation end points supported that the majority of the mitogenic effect of insulin in L6-hIR cells was mediated by the overexpressed hIR-A. Using the optimized L6-hIR assay, we found that the X-10 insulin analog was more mitogenic than native human insulin, supporting that X-10 exhibits increased mitogenic signaling through the hIR-A. In summary, this study provides the first demonstration that serum deprivation may not be sufficient, and G0/G1 synchronization may be required to obtain optimal responsiveness of hIR-overexpressing cell lines for preclinical safety testing. |
| Starting Page | 293 |
| Ending Page | 307 |
| Page Count | 15 |
| File Format | |
| ISSN | 07422091 |
| Journal | Cell Biology and Toxicology |
| Volume Number | 26 |
| Issue Number | 4 |
| e-ISSN | 15736822 |
| Language | English |
| Publisher | Springer Netherlands |
| Publisher Date | 2009-11-08 |
| Publisher Place | Dordrecht |
| Access Restriction | Subscribed |
| Subject Keyword | Flow cytometry Insulin analog Insulin receptor Mitogenic effect Molecular toxicology 3H-thymidine Biochemistry Pharmacology/Toxicology Cell Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Health, Toxicology and Mutagenesis Toxicology |
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