Document Detail


Glucocorticoid-induced suppression of β-cell proliferation is mediated by Mig6.
MedLine Citation:
PMID:  23384834     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
E Scott Colvin; Hong-Yun Ma; Yi-Chun Chen; Angelina M Hernandez; Patrick T Fueger
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-05
Journal Detail:
Title:  Endocrinology     Volume:  154     ISSN:  1945-7170     ISO Abbreviation:  Endocrinology     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-22     Completed Date:  2013-04-18     Revised Date:  2014-07-04    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1039-46     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Carrier Proteins / antagonists & inhibitors,  genetics,  metabolism*
Cell Line
Cell Proliferation / drug effects
Dexamethasone / pharmacology*
G1 Phase Cell Cycle Checkpoints / drug effects
Glucocorticoids / pharmacology
Humans
Insulin-Secreting Cells / cytology*,  drug effects*,  metabolism
Intracellular Signaling Peptides and Proteins / metabolism*
MAP Kinase Signaling System / drug effects
Male
Mice
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering / genetics
Rats
Rats, Wistar
Receptors, Glucocorticoid / metabolism
Tumor Suppressor Proteins / metabolism*
Grant Support
ID/Acronym/Agency:
DK078732/DK/NIDDK NIH HHS; R00 DK078732/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Carrier Proteins; 0/Glucocorticoids; 0/Intracellular Signaling Peptides and Proteins; 0/MIG-6 protein, human; 0/RALT protein, mouse; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Receptors, Glucocorticoid; 0/Tumor Suppressor Proteins; 0/gene 33 protein, rat; 7S5I7G3JQL/Dexamethasone
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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