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

Autor: Jörg H W Distler, Katrin Palumbo-Zerr, Oliver Distler, Gerhard Krönke, Carina Scholtysek, Michal Tomcik, Dirk Mielenz, Jingang Huang, Clara Dees, Pawel Zerr, Rossella Mancuso, Georg Schett, Daniel Metzger, Barbara G. Fürnrohr, Christian Beyer, Judith Fliehr, Alfiya Distler
Přispěvatelé: University of Zurich, Distler, Jörg H W
Rok vydání: 2015
Předmět:
Adult
Male
Adolescent
Sp1 Transcription Factor
610 Medicine & health
Histone Deacetylase 1
Biology
General Biochemistry
Genetics and Molecular Biology
Mice
Young Adult
Downregulation and upregulation
1300 General Biochemistry
Genetics and Molecular Biology
Liver Cirrhosis
Alcoholic
Transforming Growth Factor beta
Fibrosis
Nuclear Receptor Subfamily 4
Group A
Member 1
medicine
Animals
Humans
Lung
Protein kinase B
Cells
Cultured
Tissue homeostasis
Aged
Skin
Histone Demethylases
Mice
Knockout
Wound Healing
Scleroderma
Systemic
10051 Rheumatology Clinic and Institute of Physical Medicine
General Medicine
Fibroblasts
Middle Aged
medicine.disease
Idiopathic Pulmonary Fibrosis
Repressor Proteins
Sin3 Histone Deacetylase and Corepressor Complex
Liver
Nuclear receptor
Case-Control Studies
Immunology
Cancer research
Female
Signal transduction
Wound healing
Co-Repressor Proteins
Signal Transduction
Transforming growth factor
Zdroj: Nature Medicine. 21:150-158
ISSN: 1546-170X
1078-8956
Popis: 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-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β 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-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.
Databáze: OpenAIRE
Externí odkaz: