Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25581517
DOI
10.1038/nm.3777
PII: nm.3777
Knihovny.cz E-resources
- MeSH
- Liver Cirrhosis, Alcoholic metabolism pathology MeSH
- Adult MeSH
- Fibroblasts metabolism MeSH
- Fibrosis MeSH
- Histone Deacetylase 1 metabolism MeSH
- Sin3 Histone Deacetylase and Corepressor Complex MeSH
- Histone Demethylases metabolism MeSH
- Wound Healing MeSH
- Idiopathic Pulmonary Fibrosis metabolism pathology MeSH
- Nuclear Receptor Subfamily 4, Group A, Member 1 genetics metabolism physiology MeSH
- Liver metabolism pathology MeSH
- Co-Repressor Proteins metabolism MeSH
- Cells, Cultured MeSH
- Skin cytology metabolism pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Lung metabolism pathology MeSH
- Repressor Proteins metabolism MeSH
- Aged MeSH
- Signal Transduction MeSH
- Case-Control Studies MeSH
- Scleroderma, Systemic metabolism pathology MeSH
- Transforming Growth Factor beta metabolism MeSH
- Sp1 Transcription Factor metabolism MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Mice MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Histone Deacetylase 1 MeSH
- Sin3 Histone Deacetylase and Corepressor Complex MeSH
- Histone Demethylases MeSH
- Nuclear Receptor Subfamily 4, Group A, Member 1 MeSH
- Co-Repressor Proteins MeSH
- Repressor Proteins MeSH
- SIN3A transcription factor MeSH Browser
- Transforming Growth Factor beta MeSH
- Sp1 Transcription Factor MeSH
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.
Center for Research of Systemic Autoimmune Diseases University Hospital Zurich Zurich Switzerland
Department of Internal Medicine 3 University of Erlangen Nuremberg Erlangen Germany
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