Glucocorticoid-induced suppression of β-cell proliferation is mediated by Mig6

E. Scott Colvin, Hong Yun Ma, Yi Chun Chen, Angelina M. Hernandez, Patrick T. Fueger

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Glucocorticoids can cause steroid-induced diabetes or accelerate the progression to diabetes by creating systemic insulin resistance and decreasing functional β-cell mass, which is influenced by changes in β-cell function, growth, and death. The synthetic glucocorticoid agonist dexamethasone (Dex) is deleterious to functional β-cell mass by decreasing β-cell function, survival, and proliferation. However, the mechanism by which Dex decreases β-cell proliferation is unknown. Interestingly, Dex induces the transcription of an antiproliferative factor and negative regulator of epidermal growth factor receptor signaling, Mig6 (alsoknownas gene 33, RALT, and Errfi1). We, therefore, hypothesized that Dex impairs β-cell proliferation by increasing the expression of Mig6 andthereby decreasingdownstreamsignaling of epidermalgrowthfactor receptor.Wefound that Dex induced Mig6 and decreased [3H]thymidine incorporation, an index of cellular replication, in mouse, rat, and human islets. Using adenovirally delivered small interfering RNA targeted to Mig6 in rat islets,wewere able to limit the induction of Mig6 upon exposure to Dex, compared with islets treated with a control virus, and completely rescued the Dex-mediated impairment in replication. We demonstrated that both Dex and overexpression of Mig6 attenuated the phosphorylation of ERK1/2 and blocked theG1/S transition of the cell cycle. In conclusion, Mig6 functions as a molecular brake for β-cell proliferation during glucocorticoid treatment in β-cells, and thus, Mig6 may be a novel target for preventing glucocorticoid-induced impairments in functional β-cell mass.

Original languageEnglish (US)
Pages (from-to)1039-1046
Number of pages8
JournalEndocrinology
Volume154
Issue number3
DOIs
StatePublished - Mar 1 2013

ASJC Scopus subject areas

  • Endocrinology

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    Colvin, E. S., Ma, H. Y., Chen, Y. C., Hernandez, A. M., & Fueger, P. T. (2013). Glucocorticoid-induced suppression of β-cell proliferation is mediated by Mig6. Endocrinology, 154(3), 1039-1046. https://doi.org/10.1210/en.2012-1923