Overexpression of ST5, an activator of Ras, has no effect on β-cell proliferation in adult mice
| Autor: | Jia Zhang, Klaus H. Kaestner, Kristy Ou, Zhao V. Wang, Phillipp Scherer, Yang Jiao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male lcsh:Internal medicine ST5 OE ST5-overexpressing rtTA reverse tetracycline-controlled transactivator ST5 Suppression of Tumorigenicity 5 Biology Brief Communication STZ streptozotocin Diabetes Mellitus Experimental 03 medical and health sciences Mice Downregulation and upregulation Epidermal growth factor Insulin-Secreting Cells β-cell proliferation medicine Animals lcsh:RC31-1245 Molecular Biology MODY Maturity Onset Diabetes of the Young PDGF Platelet-Derived Growth Factor Cell Proliferation Doxycycline geography geography.geographical_feature_category Ras/ERK signaling RIP Rat Insulin Promoter Cell growth Activator (genetics) ST5 (Suppression Of Tumorigenicity 5) GEF Guanine Nucleotide Exchange Factor Tumor Suppressor Proteins Diabetes Cell Biology Islet Streptozotocin Up-Regulation DNA-Binding Proteins Mice Inbred C57BL EGF Epidermal Growth Factor 030104 developmental biology Cancer research Female TRE Tetracycline Response Element Signal transduction pERK phosphorylated ERK medicine.drug Signal Transduction |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 11, Iss, Pp 212-217 (2018) |
| ISSN: | 2212-8778 |
| Popis: | Objective Both Type I and Type II diabetes mellitus result from insufficient functional β-cell mass. Efforts to increase β-cell proliferation as a means to restore β-cell mass have been met with limited success. Suppression of Tumorigenicity 5 (ST5) activates Ras/Erk signaling in the presence of Epidermal Growth Factor (EGF). In the pancreatic islet, Ras/Erk signaling is required for augmented β-cell proliferation during pregnancy, suggesting that ST5 is an appealing candidate to enhance adult β-cell proliferation. We aimed to test the hypothesis that overexpression of ST5 drives adult β-cell proliferation. Methods We utilized a doxycycline-inducible bitransgenic mouse model to activate β-cell-specific expression of human ST5 in adult mice at will. Islet morphology, β-cell proliferation, and β-cell mass in control and ST5-overexpressing (ST5 OE) animals were analyzed by immunofluorescent staining, under basal and two stimulated metabolic states: pregnancy and streptozotocin (STZ)-induced β-cell loss. Results Doxycycline treatment resulted in robust ST5 overexpression in islets from 12-16 week-old ST5 OE animals compared to controls, without affecting the islet morphology and identity of the β-cells. Under both basal and metabolically stimulated pregnancy states, β-cell proliferation and mass were comparable in ST5 OE and control animals. Furthermore, there was no detectable difference in β-cell proliferation between ST5 OE and control animals in response to STZ-induced β-cell loss. Conclusions We successfully derived an inducible bitransgenic mouse model to overexpress ST5 specifically in β-cells. However, our findings demonstrate that ST5 overexpression by itself has no mitogenic effect on the adult β-cell under basal and metabolically challenged states. Highlights • Hypothesized that overexpression of ST5 would drive adult β-cell proliferation due to its role in activating MAPK/ERK. • Generated a doxycycline-inducible bitransgenic mouse model to activate β-cell-specific expression of ST5. • ST5 overexpression has no mitogenic effect on adult β-cellsunder basal and metabolically challenged states. |
| Databáze: | OpenAIRE |
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