Overexpression of ST5, an activator of Ras, has no effect on β-cell proliferation in adult mice

Kristy Ou, Jia Zhang, Yang Jiao, Zhao V. Wang, Phillipp Scherer, Klaus H. Kaestner

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalMolecular Metabolism
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • Diabetes
  • Ras/ERK signaling
  • ST5 (Suppression Of Tumorigenicity 5)
  • β-cell proliferation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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