Glucocorticoids and checkpoint tyrosine kinase inhibitors stimulate rat pancreatic beta cell proliferation differentially
| Autor: | Jordy Stichelmans, Sarah Akbib, Karine Hellemans, Geert Stangé, Zerihun Assefa, Zhidong Ling |
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| Přispěvatelé: | Faculty of Medicine and Pharmacy, Diabetes Pathology & Therapy, Pathology/molecular and cellular medicine, Medicine and Pharmacy academic/administration, Diabetes Clinic |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cell division Kinase Inhibitors Synthesis Phase Biochemistry S Phase Mathematical and Statistical Techniques 0302 clinical medicine Insulin-Secreting Cells Cell Cycle and Cell Division Enzyme Inhibitors Multidisciplinary Agricultural and Biological Sciences(all) Chromosome Biology Chemistry Statistics Middle Aged Cell cycle 3. Good health Cell biology Cell Processes Physical Sciences Medicine Female Beta cell Restriction point Tyrosine kinase Research Article Adult Science Mitosis 030209 endocrinology & metabolism Research and Analysis Methods 03 medical and health sciences Cyclins CDC2 Protein Kinase Animals Humans Statistical Methods Glucocorticoids Protein Kinase Inhibitors Cell Cycle Inhibitors Aged Cell Proliferation Analysis of Variance Cyclin-dependent kinase 1 Cell growth Biochemistry Genetics and Molecular Biology(all) G1 Phase Biology and Life Sciences Cell Biology Rats 030104 developmental biology Checkpoint Kinase 1 Enzymology Mathematics |
| Zdroj: | PLOS ONE PLoS ONE PLoS ONE, Vol 14, Iss 2, p e0212210 (2019) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0212210 |
| Popis: | Cell therapy for diabetes could benefit from the identification of small-molecule compounds that increase the number of functional pancreatic beta cells. Using a newly developed screening assay, we previously identified glucocorticoids as potent stimulators of human and rat beta cell proliferation. We now compare the stimulatory action of these steroid hormones to a selection of checkpoint tyrosine kinase inhibitors that were also found to activate the cell cycle-in beta cells and analyzed their respective effects on DNA-synthesis, beta cell numbers and expression of cell cycle regulators. Our data using glucocorticoids in combination with a receptor antagonist, mifepristone, show that 48h exposure is sufficient to allow beta cells to pass the cell cycle restriction point and to become committed to cell division regardless of sustained glucocorticoid-signaling. To reach the end-point of mitosis another 40h is required. Within 14 days glucocorticoids stimulate up to 75% of the cells to undergo mitosis, which indicates that these steroid hormones act as proliferation competence-inducing factors. In contrast, by correlating thymidine-analogue incorporation to changes in absolute cell numbers, we show that the checkpoint kinase inhibitors, as compared to glucocorticoids, stimulate DNA-synthesis only during a short time-window in a minority of cells, insufficient to give a measurable increase of beta cell numbers. Glucocorticoids, but not the kinase inhibitors, were also found to induce changes in the expression of checkpoint regulators. Our data, using checkpoint kinase-specific inhibitors further point to a role for Chk1 and Cdk1 in G1/S transition and progression of beta cells through the cell cycle upon stimulation with glucocorticoids. |
| Databáze: | OpenAIRE |
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