Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis

被引：296

作者：

Palumbo-Zerr, Katrin ^{[1
]}

Zerr, Pawel ^{[1
]}

Distler, Alfiya ^{[1
]}

Fliehr, Judith ^{[1
]}

Mancuso, Rossella ^{[1
]}

Huang, Jingang ^{[1
]}

Mielenz, Dirk ^{[2
]}

Tomcik, Michal ^{[1
,3
,4
]}

Fuernrohr, Barbara G. ^{[2
,5
]}

Scholtysek, Carina ^{[1
]}

Dees, Clara ^{[1
]}

Beyer, Christian ^{[1
]}

Kroenke, Gerhard ^{[1
]}

Metzger, Daniel ^{[6
]}

Distler, Oliver ^{[7
]}

Schettl, Georg ^{[1
]}

Distler, Joerg H. W. ^{[1
]}

机构：

[1] Univ Erlangen Nurnberg, Dept Internal Med 3, D-91054 Erlangen, Germany

[2] Univ Erlangen Nurnberg, Dept Internal Med 3, Nikolaus Fiebiger Ctr, Div Mol Immunol, D-91054 Erlangen, Germany

[3] Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic

[4] Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic

[5] Med Univ Innsbruck, Div Biol Chem, A-6020 Innsbruck, Austria

[6] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire, INSERM, CNRS UMR7104,U964, Illkirch Graffenstaden, France

[7] Univ Zurich Hosp, Ctr Res Syst Autoimmune Dis, CH-8091 Zurich, Switzerland

来源：

NATURE MEDICINE | 2015年 / 21卷 / 02期

关键词：

MECHANISMS; KINASE; DIFFERENTIATION; ACTIVATION; EXPRESSION; RESPONSES; MURINE; REPAIR; CELLS; MODEL;

D O I：

10.1038/nm.3777

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-beta (TGF-beta) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-beta target genes, thereby limiting pro-fibrotic TGF-beta effects. Even though temporary upregulation of TGF-beta in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-beta signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-beta signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.

引用

页码：150 / 158

页数：9

共 35 条

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