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Glucocorticoid-induced suppression of beta-cell proliferation is mediated by Mig6.

Authors: Colvin, ES  Ma, HY  Chen, YC  Hernandez, AM  Fueger, PT 
Citation: Colvin ES, etal., Endocrinology. 2013 Mar;154(3):1039-46. doi: 10.1210/en.2012-1923. Epub 2013 Feb 5.
Pubmed: (View Article at PubMed) PMID:23384834
DOI: Full-text: DOI:10.1210/en.2012-1923

Glucocorticoids can cause steroid-induced diabetes or accelerate the progression to diabetes by creating systemic insulin resistance and decreasing functional beta-cell mass, which is influenced by changes in beta-cell function, growth, and death. The synthetic glucocorticoid agonist dexamethasone (Dex) is deleterious to functional beta-cell mass by decreasing beta-cell function, survival, and proliferation. However, the mechanism by which Dex decreases beta-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 beta-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 beta-cell proliferation during glucocorticoid treatment in beta-cells, and thus, Mig6 may be a novel target for preventing glucocorticoid-induced impairments in functional beta-cell mass.


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CRRD Object Information
CRRD ID: 9685543
Created: 2015-01-19
Species: All species
Last Modified: 2015-01-19
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.