TY - JOUR
T1 - Overexpression of ST5, an activator of Ras, has no effect on β-cell proliferation in adult mice
AU - Ou, Kristy
AU - Zhang, Jia
AU - Jiao, Yang
AU - Wang, Zhao V.
AU - Scherer, Phillipp
AU - Kaestner, Klaus H.
N1 - Funding Information:
We thank the Morphology Core of the Penn Center for Molecular Studies in Liver and Digestive Disease (P30-DK050306) for reagents and technical assistance. This work was funded by JDRF 17-2011-262 and NIH grants UC4DK104119 and R01-DK088383 to KHK.
Funding Information:
We thank the Morphology Core of the Penn Center for Molecular Studies in Liver and Digestive Disease (P30-DK050306) for reagents and technical assistance. This work was funded by JDRF 17-2011-262 and NIH grants UC4DK104119 and R01-DK088383 to KHK .
Publisher Copyright:
© 2018 The Authors
PY - 2018/5
Y1 - 2018/5
N2 - 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.
AB - 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.
KW - Diabetes
KW - Ras/ERK signaling
KW - ST5 (Suppression Of Tumorigenicity 5)
KW - β-cell proliferation
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U2 - 10.1016/j.molmet.2018.03.009
DO - 10.1016/j.molmet.2018.03.009
M3 - Article
C2 - 29650351
AN - SCOPUS:85045094185
SN - 2212-8778
VL - 11
SP - 212
EP - 217
JO - Molecular Metabolism
JF - Molecular Metabolism
ER -