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

Endocrinology. 2013 Mar;154(3):1039-46. doi: 10.1210/en.2012-1923. Epub 2013 Feb 5.

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 (also known as gene 33, RALT, and Errfi1). We, therefore, hypothesized that Dex impairs β-cell proliferation by increasing the expression of Mig6 and thereby decreasing downstream signaling of epidermal growth factor receptor. We found that Dex induced Mig6 and decreased [(3)H]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, we were 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 the G(1)/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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Proliferation / drug effects
  • Dexamethasone / pharmacology*
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Glucocorticoids / pharmacology
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Wistar
  • Receptors, Glucocorticoid / metabolism
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Errfi1 protein, mouse
  • Glucocorticoids
  • Intracellular Signaling Peptides and Proteins
  • MIG-6 protein, human
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Glucocorticoid
  • Tumor Suppressor Proteins
  • gene 33 protein, rat
  • Dexamethasone