title: SRA regulates adipogenesis by modulating p38/JNK phosphorylation and stimulating insulin receptor gene expression and downstream signaling.
abstract: The Steroid Receptor RNA Activator (SRA) enhances adipogenesis and increases both glucose uptake and phosphorylation of Akt and FOXO1 in response to insulin. To assess the mechanism, we differentiated ST2 mesenchymal precursor cells that did or did not overexpress SRA into adipocytes using combinations of methylisobutylxanthine, dexamethasone and insulin. These studies showed that SRA overexpression promotes full adipogenesis in part by stimulation of insulin/insulin-like growth factor-1 (IGF-1) signaling. SRA overexpression inhibited phosphorylation of p38 mitogen activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) in the early differentiation of ST2 cells. Conversely, knockdown of endogenous SRA in 3T3-L1 cells increased phosphorylation of JNK. Knockdown of SRA in mature 3T3-L1 adipocytes reduced insulin receptor (IR) mRNA and protein levels, which led to decreased autophosphorylation of IRβ and decreased phosphorylation of insulin receptor substrate-1 (IRS-1) and Akt. This likely reflects a stimulatory role of SRA on IR transcription, as transfection studies showed that SRA increased expression of an IR promoter-luciferase reporter construct.
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Shannon
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Ruichuan
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gerin
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: William P
authors.initials: WP
authors.lastname: Cawthorn
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America; Department of Molecular & Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Ormond A
authors.initials: OA
authors.lastname: Macdougald
authors.affiliation: Life Science Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Chen
authors.affiliation: Life Science Institute, University of Michigan, Ann Arbor, Michigan, United States of America; Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Koenig
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
mesh_terms: D016475:3T3 Cells; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D062085:RNA, Long Noncoding; C405423:steroid receptor RNA activator; D011972:Receptor, Insulin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
references.citation: Dev Cell. 2002 Jul;3(1):39-49
references.pmid: 12110166
references.citation: Metabolism. 1980 May;29(5):455-66
references.pmid: 6990180
references.citation: Science. 2000 Aug 11;289(5481):950-3
references.pmid: 10937998
references.citation: Science. 1991 Aug 2;253(5019):565-8
references.pmid: 1857988
references.citation: EMBO J. 1995 Feb 15;14(4):674-84
references.pmid: 7882971
references.citation: J Clin Invest. 1976 Dec;58(6):1435-41
references.pmid: 993352
references.citation: Diabetes. 2006 Feb;55(2):281-9
references.pmid: 16443758
references.citation: Biosci Biotechnol Biochem. 2003 Feb;67(2):314-21
references.pmid: 12728992
references.citation: PLoS One. 2010 Dec 02;5(12):e14199
references.pmid: 21152033
references.citation: Breast Cancer Res. 2009;11(5):R67
references.pmid: 19740422
references.citation: J Biol Chem. 2004 Aug 6;279(32):33051-6
references.pmid: 15180993
references.citation: Nature. 2001 Dec 13;414(6865):799-806
references.pmid: 11742412
references.citation: Cell Metab. 2006 Oct;4(4):263-73
references.pmid: 17011499
references.citation: Mol Cell Biol. 2001 Apr;21(7):2521-32
references.pmid: 11259600
references.citation: Biochem Biophys Res Commun. 2003 Feb 7;301(2):509-15
references.pmid: 12565891
references.citation: Dev Cell. 2006 Oct;11(4):547-60
references.pmid: 17011493
references.citation: EMBO J. 1996 Jun 3;15(11):2760-70
references.pmid: 8654373
references.citation: J Biol Chem. 2005 Oct 21;280(42):35361-71
references.pmid: 16085647
references.citation: Trends Endocrinol Metab. 2012 Feb;23(2):56-64
references.pmid: 22079269
references.citation: Mol Cell Biol. 2009 Apr;29(7):1719-34
references.pmid: 19188450
references.citation: Biochem J. 2003 Jan 1;369(Pt 1):163-71
references.pmid: 12350225
references.citation: Cell Metab. 2008 Apr;7(4):339-47
references.pmid: 18396140
references.citation: Nat Rev Mol Cell Biol. 2011 Sep 28;12(11):722-34
references.pmid: 21952300
references.citation: PLoS One. 2009 Jul 10;4(7):e6189
references.pmid: 19593385
references.citation: Nat Rev Mol Cell Biol. 2006 Dec;7(12):885-96
references.pmid: 17139329
references.citation: Nucleic Acids Res. 2011 Jan;39(2):513-25
references.pmid: 20855289
references.citation: Cell Mol Life Sci. 2007 Apr;64(7-8):873-91
references.pmid: 17347799
references.citation: FEBS Lett. 2004 May 21;566(1-3):43-7
references.pmid: 15147866
references.citation: Cell Metab. 2013 Feb 5;17(2):197-209
references.pmid: 23395167
references.citation: Biochimie. 2005 Jan;87(1):51-6
references.pmid: 15733737
references.citation: J Biol Chem. 2000 Mar 24;275(12):9047-54
references.pmid: 10722755
references.citation: Metabolism. 1980 May;29(5):467-73
references.pmid: 6990181
references.citation: Mol Pharmacol. 1992 Feb;41(2):393-8
references.pmid: 1538716
references.citation: Mol Cell Biol. 2004 Mar;24(5):1918-29
references.pmid: 14966273
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16081-6
references.pmid: 12444263
references.citation: Nat Rev Mol Cell Biol. 2006 Feb;7(2):85-96
references.pmid: 16493415
references.citation: Diabetologia. 2005 Nov;48(11):2203-5
references.pmid: 16193286
references.citation: Genes Dev. 2003 Jun 1;17(11):1352-65
references.pmid: 12782654
references.citation: Mol Cell Biol. 2003 Oct;23(20):7163-76
references.pmid: 14517287
references.citation: Mol Cell. 2004 Aug 27;15(4):549-58
references.pmid: 15327771
references.citation: Mol Endocrinol. 2002 May;16(5):1040-8
references.pmid: 11981038
references.citation: Mol Cancer Ther. 2006 Dec;5(12):2970-6
references.pmid: 17172402
references.citation: Biochem J. 2002 Nov 1;367(Pt 3):577-85
references.pmid: 12167088
references.citation: Nature. 2006 Dec 14;444(7121):847-53
references.pmid: 17167472
references.citation: Nature. 2002 Nov 21;420(6913):333-6
references.pmid: 12447443
references.citation: J Biol Chem. 2007 May 11;282(19):14515-24
references.pmid: 17351296
references.citation: Cell. 1975 May;5(1):19-27
references.pmid: 165899
references.citation: J Clin Invest. 2003 Jul;112(2):197-208
references.pmid: 12843127
references.citation: Cell. 1999 Apr 2;97(1):17-27
references.pmid: 10199399