Orphan nuclear receptor NR4A1 regulates transforming growth factor-β 2 signaling and fibrosis

Nature Medicine

Volumn 21, Issue 2, 2015, Pages 150-158

  Palumbo Zerr, Katrin ^a   Zerr, Pawel ^a   Distler, Alfiya ^a   Fliehr, Judith ^a   Mancuso, Rossella ^a   Huang, Jingang ^a   Mielenz, Dirk ^a   Tomcik, Michal ^a,b   Fürnrohr, Barbara G ^a,c   Scholtysek, Carina ^a   Dees, Clara ^a   Beyer, Christian ^a   Krönke, Gerhard ^a   Metzger, Daniel ^d   Distler, Oliver ^e   Schett, Georg ^a   Distler, Jörg H W ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

^b CHARLES UNIVERSITY   (Czech Republic)

^c INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^d UNIVERSITÉ DE STRASBOURG   (France)

^e UNIVERSITY HOSPITAL ZURICH   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

HISTONE DEACETYLASE 1; NUCLEAR RECEPTOR NUR77; ORPHAN NUCLEAR RECEPTOR; TRANSCRIPTION FACTOR SIN3A; TRANSCRIPTION FACTOR SP1; TRANSFORMING GROWTH FACTOR BETA; COREPRESSOR PROTEIN; HISTONE DEMETHYLASE; REPRESSOR PROTEIN; SIN3A TRANSCRIPTION FACTOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; ENZYME ACTIVATION; FIBROSIS; HOMEOSTASIS; HUMAN; HUMAN CELL; HUMAN TISSUE; KIDNEY FIBROSIS; LIVER FIBROSIS; LUNG FIBROSIS; MOUSE; NEGATIVE FEEDBACK; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; SKIN FIBROSIS; UPREGULATION; WOUND HEALING; ADOLESCENT; ADULT; AGED; ALCOHOL LIVER CIRRHOSIS; ANIMAL; CASE CONTROL STUDY; CELL CULTURE; CYTOLOGY; FEMALE; FIBROBLAST; FIBROSING ALVEOLITIS; GENETICS; KNOCKOUT MOUSE; LIVER; LUNG; MALE; METABOLISM; MIDDLE AGED; PATHOLOGY; PHYSIOLOGY; SKIN; SYSTEMIC SCLEROSIS; YOUNG ADULT;

ADOLESCENT; ADULT; AGED; ANIMALS; CASE-CONTROL STUDIES; CELLS, CULTURED; CO-REPRESSOR PROTEINS; FEMALE; FIBROBLASTS; FIBROSIS; HISTONE DEACETYLASE 1; HISTONE DEMETHYLASES; HUMANS; IDIOPATHIC PULMONARY FIBROSIS; LIVER; LIVER CIRRHOSIS, ALCOHOLIC; LUNG; MALE; MICE; MICE, KNOCKOUT; MIDDLE AGED; NUCLEAR RECEPTOR SUBFAMILY 4, GROUP A, MEMBER 1; REPRESSOR PROTEINS; SCLERODERMA, SYSTEMIC; SIGNAL TRANSDUCTION; SKIN; SP1 TRANSCRIPTION FACTOR; TRANSFORMING GROWTH FACTOR BETA; WOUND HEALING; YOUNG ADULT;

EID: 84925537240     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.3777     Document Type: Article

References (45)

1. Wynn, T.A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199-210 (2008).
2. Massagué, J. TGF? signalling in context. Nat. Rev. Mol. Cell Biol. 13, 616-630 (2012).
3. Gurtner, G.C., Werner, S., Barrandon, Y. & Longaker, M.T. Wound repair and regeneration. Nature 453, 314-321 (2008).
4. Gabrielli, A., Avvedimento, E.V. & Krieg, T. Scleroderma. N. Engl. J. Med. 360, 1989-2003 (2009).
5. Duffield, J.S., Lupher, M., Thannickal, V.J. & Wynn, T.A. Host responses in tissue repair and fibrosis. Annu. Rev. Pathol. 8, 241-276 (2013).
6. Beyer, C. et al. Activation of pregnane X receptor inhibits experimental dermal fibrosis. Ann. Rheum. Dis. 72, 621-625 (2013).
7. Zerr, P. et al. Vitamin D receptor regulates TGF-? signalling in systemic sclerosis. Ann. Rheum. Dis. doi:10.1136/annrheumdis-2013-204378 (21 January 2014).
8. Wu, M. et al. Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-?. Am. J. Pathol. 174, 519-533 (2009).
9. Milbrandt, J. Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1, 183-188 (1988).
10. Maxwell, M.A. et al. Nur77 regulates lipolysis in skeletal muscle cells. Evidence for cross-talk between the beta-adrenergic and an orphan nuclear hormone receptor pathway. J. Biol. Chem. 280, 12573-12584 (2005).
11. Pei, L. et al. NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nat. Med. 12, 1048-1055 (2006).
12. Fassett, M.S., Jiang, W., D'Alise, A.M., Mathis, D. & Benoist, C. Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion. Proc. Natl. Acad. Sci. USA 109, 3891-3896 (2012).
13. Hanna, R.N. et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C? monocytes. Nat. Immunol. 12, 778-785 (2011).
14. Zeng, H. et al. Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity. J. Exp. Med. 203, 719-729 (2006).
15. Arkenbout, E.K. et al. Protective function of transcription factor TR3 orphan receptor in atherogenesis: decreased lesion formation in carotid artery ligation model in TR3 transgenic mice. Circulation 106, 1530-1535 (2002).
16. Han, Y.H. et al. Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt. Oncogene 25, 2974-2986 (2006).
17. Chen, H.Z. et al. The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling. Gut 61, 714-724 (2012).
18. Zhan, Y. et al. Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nat. Chem. Biol. 4, 548-556 (2008).
19. Uhl, M. et al. SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res. 64, 7954-7961 (2004).
20. Datta, P.K., Blake, M.C. & Moses, H.L. Regulation of plasminogen activator inhibitor-1 expression by transforming growth factor-beta -induced physical and functional interactions between smads and Sp1. J. Biol. Chem. 275, 40014-40019 (2000).
21. Loeys, B.L. et al. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci. Transl. Med. 2, 23-20 (2010).
22. Pascual, G. & Glass, C.K. Nuclear receptors versus inflammation: mechanisms of transrepression. Trends Endocrinol. Metab. 17, 321-327 (2006).
23. Lee, S.O. et al. Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth. Cancer Res. 70, 6824-6836 (2010).
24. Poncelet, A.C. & Schnaper, H.W. Sp1 and Smad proteins cooperate to mediate transforming growth factor-beta 1-induced alpha 2(I) collagen expression in human glomerular mesangial cells. J. Biol. Chem. 276, 6983-6992 (2001).
25. Zhou, F. et al. Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-? signalling. Nat. Commun. 5, 3388 (2014).
26. Sonnylal, S. et al. Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum. 56, 334-344 (2007).
27. Galiano, R.D., Michaels, J.t., Dobryansky, M., Levine, J.P. & Gurtner, G.C. Quantitative and reproducible murine model of excisional wound healing. Wound Repair Regen. 12, 485-492 (2004).
28. Wong, V.W., Sorkin, M., Glotzbach, J.P., Longaker, M.T. & Gurtner, G.C. Surgical approaches to create murine models of human wound healing. J. Biomed. Biotechnol. 2011, 969618 (2011).
29. Lin, B. et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116, 527-540 (2004).
30. Mullican, S.E. et al. Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat. Med. 13, 730-735 (2007).
31. Beyer, C. & Distler, J.H. Tyrosine kinase signaling in fibrotic disorders: Translation of basic research to human disease. Biochim. Biophys. Acta 7, 897-904 (2013).
32. Lee, S.O. et al. The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53. Oncogene 31, 3265-3276 (2012).
33. Li, H. et al. Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science 289, 1159-1164 (2000).
34. Thompson, J. & Winoto, A. During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain. J. Exp. Med. 205, 1029-1036 (2008).
35. Liu, J.J. et al. A unique pharmacophore for activation of the nuclear orphan receptor Nur77 in vivo and in vitro. Cancer Res. 70, 3628-3637 (2010).
36. Lee, S.L. et al. Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science 269, 532-535 (1995).
37. Dees, C. et al. Platelet-derived serotonin links vascular disease and tissue fibrosis. J. Exp. Med. 208, 961-972 (2011).
38. Wieser, R., Wrana, J.L. & Massague, J. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-? receptor complex. EMBO J. 14, 2199-2208 (1995).
39. Akhmetshina, A. et al. Activation of canonical Wnt signalling is required for TGF-?-mediated fibrosis. Nat. Commun. 3, 735 (2012).
40. Hecker, L. et al. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat. Med. 15, 1077-1081 (2009).
41. Hernández-Gea, V. et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938-946 (2012).
42. Moles, A. et al. A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse. J. Hepatol. 60, 782-791 (2014).
43. Bechtel, W. et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 16, 544-550 (2010).
44. Zeisberg, M. et al. BMP-7 counteracts TGF-?1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9, 964-968 (2003).
45. Wendling, O., Bornert, J.M., Chambon, P. & Metzger, D. Efficient temporally-controlled targeted mutagenesis in smooth muscle cells of the adult mouse. Genesis 47, 14-18 (2009).