title: Glucocorticoid-induced suppression of β-cell proliferation is mediated by Mig6.
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.
authors: Department of Pediatrics and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: E Scott
authors: ES
authors: Colvin
authors: Hong-Yun
authors: HY
authors: Ma
authors: Yi-Chun
authors: YC
authors: Chen
authors: Angelina M
authors: AM
authors: Hernandez
authors: Patrick T
authors: PT
authors: Fueger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C484017:ERRFI1 protein, human; C475819:Errfi1 protein, mouse; C000629925:Errfi1 protein, rat; D005938:Glucocorticoids; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D025521:Tumor Suppressor Proteins; D003907:Dexamethasone
references: Mol Endocrinol. 2013 Jan;27(1):162-71
references: 23204325
references: J Biol Chem. 1995 Jan 20;270(3):1295-9
references: 7836394
references: Anal Biochem. 1993 Feb 1;208(2):397-9
references: 8095775
references: Biochem J. 1997 Feb 1;321 ( Pt 3):707-12
references: 9032457
references: Diabetes. 2006 Feb;55(2):318-25
references: 16443763
references: Nat Protoc. 2009;4(11):1649-52
references: 19876025
references: Am J Respir Cell Mol Biol. 2002 Sep;27(3):320-8
references: 12204894
references: Endocrinology. 2009 Sep;150(9):4065-73
references: 19443572
references: Postgrad Med J. 1964 Nov;40:660-9
references: 14230307
references: J Mol Endocrinol. 2008 Jul;41(1):35-44
references: 18487229
references: J Vis Exp. 2012 Jun 25;(64):
references: 22760342
references: Pharmacol Ther. 2002 Oct;96(1):23-43
references: 12441176
references: Endocrinology. 1989 Feb;124(2):754-61
references: 2643510
references: Mol Cell Biol. 1999 Sep;19(9):6003-11
references: 10454547
references: Nat Med. 2006 May;12(5):568-73
references: 16648858
references: Diabetes. 2000 Mar;49(3):424-30
references: 10868964
references: Proc Natl Acad Sci U S A. 2005 May 17;102(20):7297-302
references: 15883383
references: Mol Biol Cell. 2001 Mar;12(3):725-38
references: 11251083
references: Trends Endocrinol Metab. 2010 Mar;21(3):151-8
references: 20015659
references: Hepatology. 2010 Apr;51(4):1383-90
references: 20044804
references: Mol Endocrinol. 2009 Jun;23(6):747-58
references: 19196831
references: Endocrinology. 2011 May;152(5):1779-88
references: 21385937
references: Rheum Dis Clin North Am. 1999 Aug;25(3):489-505
references: 10467625
references: J Biol Chem. 2005 Jan 28;280(4):2924-33
references: 15556944
references: Mol Endocrinol. 2008 May;22(5):1251-9
references: 18258687
references: Am J Physiol Gastrointest Liver Physiol. 2007 Sep;293(3):G552-9
references: 17585012
references: Oncogene. 2007 Jan 11;26(2):269-76
references: 16819504
references: Endocrinology. 2003 Feb;144(2):412-22
references: 12538600
references: Diabetes. 2004 Sep;53(9):2190-4
references: 15331526
references: Diabetologia. 1980 Nov;19(5):439-44
references: 7004962
references: Physiol Rev. 2005 Oct;85(4):1255-70
references: 16183912
references: Diabetologia. 2005 Oct;48(10):2119-30
references: 16078016
references: Diabetes. 1995 Mar;44(3):249-56
references: 7883109
references: Methods Cell Biol. 1994;43 Pt A:161-89
references: 7823861
references: J Cell Biol. 2005 Oct 24;171(2):337-48
references: 16247031
references: J Clin Invest. 1997 Oct 15;100(8):2094-8
references: 9329975
references: Nurs Clin North Am. 2001 Jun;36(2):333-9, viii
references: 11382567
references: Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6912-7
references: 20351267
references: Genesis. 2007 Nov;45(11):716-21
references: 17987665
references: J Cell Biol. 2010 May 3;189(3):557-71
references: 20421427
references: Endocrinology. 2000 Apr;141(4):1384-93
references: 10746642
references: N Engl J Med. 2000 Jul 27;343(4):230-8
references: 10911004
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2509-14
references: 9482916
references: Diabetes. 2004 Dec;53 Suppl 3:S16-21
references: 15561905
references: Am J Physiol. 1997 Aug;273(2 Pt 1):E315-20
references: 9277384
references: Diabetes. 2006 May;55(5):1380-90
references: 16644695
references: Mol Cell Biol. 2008 May;28(10):3465-76
references: 18347054
references: Pancreas. 2003 May;26(4):e99-104
references: 12717280
references: Nature. 2007 Nov 29;450(7170):741-4
references: 18046415