Advertisement

Cellular and Molecular Life Sciences

, Volume 73, Issue 20, pp 3789–3800 | Cite as

Nuclear receptor function in skin health and disease: therapeutic opportunities in the orphan and adopted receptor classes

  • Kelvin Yin
  • Aaron G. SmithEmail author
Multi-author review

Abstract

The skin forms a vital barrier between an organism’s external environment, providing protection from pathogens and numerous physical and chemical threats. Moreover, the intact barrier is essential to prevent water and electrolyte loss without which terrestrial life could not be maintained. Accordingly, acute disruption of the skin through physical or chemical trauma needs to be repaired timely and efficiently as sustained skin pathologies ranging from mild irritations and inflammation through to malignancy impact considerably on morbidity and mortality. The Nuclear Hormone Receptor Family of transcriptional regulators has proven to be highly valuable targets for addressing a range of pathologies, including metabolic syndrome and cancer. Indeed members of the classic endocrine sub-group, such as the glucocorticoid, retinoid, and Vitamin D receptors, represent mainstay treatment strategies for numerous inflammatory skin disorders, though side effects from prolonged use are common. Emerging evidence has now highlighted important functional roles for nuclear receptors belonging to the adopted and orphan subgroups in skin physiology and patho-physiology. This review will focus on these subgroups and explore the current evidence that suggests these nuclear receptor hold great promise as future stand-alone or complementary drug targets in treating common skin diseases and maintaining skin homeostasis.

Keywords

Nuclear receptor Wound healing Orphan receptors PPAR LXR NR4A 

References

  1. 1.
    Elias PM et al (2002) Basis for the permeability barrier abnormality in lamellar ichthyosis. Exp Dermatol 11(3):248–256PubMedCrossRefGoogle Scholar
  2. 2.
    Schmuth M et al (2004) Structural and functional consequences of loricrin mutations in human loricrin keratoderma (Vohwinkel syndrome with ichthyosis). J Invest Dermatol 122(4):909–922PubMedCrossRefGoogle Scholar
  3. 3.
    Albanesi C, Pastore S (2010) Pathobiology of chronic inflammatory skin diseases: interplay between keratinocytes and immune cells as a target for anti-inflammatory drugs. Curr Drug Metab 11(3):210–227PubMedCrossRefGoogle Scholar
  4. 4.
    Lin JY, Fisher DE (2007) Melanocyte biology and skin pigmentation. Nature 445(7130):843–850PubMedCrossRefGoogle Scholar
  5. 5.
    Feingold KR, Elias PM (2014) Role of lipids in the formation and maintenance of the cutaneous permeability barrier. Biochim Biophys Acta 1841(3):280–294PubMedCrossRefGoogle Scholar
  6. 6.
    Proksch E, Brandner JM, Jensen JM (2008) The skin: an indispensable barrier. Exp Dermatol 17(12):1063–1072PubMedCrossRefGoogle Scholar
  7. 7.
    van Smeden J et al (2014) The important role of stratum corneum lipids for the cutaneous barrier function. Biochim Biophys Acta 1841(3):295–313PubMedCrossRefGoogle Scholar
  8. 8.
    Rieger S et al (2015) The role of nuclear hormone receptors in cutaneous wound repair. Cell Biochem Funct 33(1):1–13PubMedCrossRefGoogle Scholar
  9. 9.
    Taylor JS (2015) Biomolecules. The dark side of sunlight and melanoma. Science 347(6224):824PubMedCrossRefGoogle Scholar
  10. 10.
    Narayanan DL, Saladi RN, Fox JL (2010) Ultraviolet radiation and skin cancer. Int J Dermatol 49(9):978–986PubMedCrossRefGoogle Scholar
  11. 11.
    Gilchrest BA et al (1999) The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med 340(17):1341–1348PubMedCrossRefGoogle Scholar
  12. 12.
    Soehnge H, Ouhtit A, Ananthaswamy ON (1997) Mechanisms of induction of skin cancer by UV radiation. Front Biosci 2:d538–d551PubMedCrossRefGoogle Scholar
  13. 13.
    Sturm RA (2009) Molecular genetics of human pigmentation diversity. Hum Mol Genet 18(R1):R9–R17PubMedCrossRefGoogle Scholar
  14. 14.
    Cleaver JE (2005) Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer 5(7):564–573PubMedCrossRefGoogle Scholar
  15. 15.
    Nagpal S (2003) An orphan meets family members in skin. J Invest Dermatol 120(2):viii–xGoogle Scholar
  16. 16.
    Hengge UR et al (2006) Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol 54(1):1–15 (Quiz 8–16) Google Scholar
  17. 17.
    Schacke H, Docke WD, Asadullah K (2002) Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 96(1):23–43PubMedCrossRefGoogle Scholar
  18. 18.
    Schoepe S et al (2006) Glucocorticoid therapy-induced skin atrophy. Exp Dermatol 15(6):406–420PubMedCrossRefGoogle Scholar
  19. 19.
    Sheu HM et al (1997) Depletion of stratum corneum intercellular lipid lamellae and barrier function abnormalities after long-term topical corticosteroids. Br J Dermatol 136(6):884–890PubMedCrossRefGoogle Scholar
  20. 20.
    Kao JS et al (2003) Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid synthesis accounts for functional abnormalities. J Invest Dermatol 120(3):456–464PubMedCrossRefGoogle Scholar
  21. 21.
    Ashwell JD, Lu FW, Vacchio MS (2000) Glucocorticoids in T cell development and function*. Annu Rev Immunol 18:309–345PubMedCrossRefGoogle Scholar
  22. 22.
    Smith AG, Muscat GE (2005) Skeletal muscle and nuclear hormone receptors: implications for cardiovascular and metabolic disease. Int J Biochem Cell Biol 37(10):2047–2063PubMedCrossRefGoogle Scholar
  23. 23.
    Michalik L, Wahli W (2007) Peroxisome proliferator-activated receptors (PPARs) in skin health, repair and disease. Biochim Biophys Acta 1771(8):991–998PubMedCrossRefGoogle Scholar
  24. 24.
    Wahli W, Michalik L (2012) PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab 23(7):351–363PubMedCrossRefGoogle Scholar
  25. 25.
    Braissant O et al (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137(1):354–366PubMedGoogle Scholar
  26. 26.
    Rivier M et al (1998) Differential expression of peroxisome proliferator-activated receptor subtypes during the differentiation of human keratinocytes. J Invest Dermatol 111(6):1116–1121PubMedCrossRefGoogle Scholar
  27. 27.
    Westergaard M et al (2003) Expression and localization of peroxisome proliferator-activated receptors and nuclear factor kappaB in normal and lesional psoriatic skin. J Invest Dermatol 121(5):1104–1117PubMedCrossRefGoogle Scholar
  28. 28.
    Fluhr JW et al (2009) Topical peroxisome proliferator activated receptor activators accelerate postnatal stratum corneum acidification. J Invest Dermatol 129(2):365–374PubMedCrossRefGoogle Scholar
  29. 29.
    Hatano Y et al (2011) Efficacy of combined peroxisome proliferator-activated receptor-alpha ligand and glucocorticoid therapy in a murine model of atopic dermatitis. J Invest Dermatol 131(9):1845–1852PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Jung K et al (2011) Peroxisome proliferator-activated receptor gamma-mediated suppression of dendritic cell function prevents the onset of atopic dermatitis in NC/Tnd mice. J Allergy Clin Immunol 127(2):420–429 (e1–6) Google Scholar
  31. 31.
    Mastrofrancesco A et al (2014) Preclinical studies of a specific PPARgamma modulator in the control of skin inflammation. J Invest Dermatol 134(4):1001–1011PubMedCrossRefGoogle Scholar
  32. 32.
    Sheu MY et al (2002) Topical peroxisome proliferator activated receptor-alpha activators reduce inflammation in irritant and allergic contact dermatitis models. J Invest Dermatol 118(1):94–101PubMedCrossRefGoogle Scholar
  33. 33.
    Hanley K et al (1998) Keratinocyte differentiation is stimulated by activators of the nuclear hormone receptor PPARalpha. J Invest Dermatol 110(4):368–375PubMedCrossRefGoogle Scholar
  34. 34.
    Komuves LG et al (1998) Ligands and activators of nuclear hormone receptors regulate epidermal differentiation during fetal rat skin development. J Invest Dermatol 111(3):429–433PubMedCrossRefGoogle Scholar
  35. 35.
    Mao-Qiang M et al (2004) Peroxisome-proliferator-activated receptor (PPAR)-gamma activation stimulates keratinocyte differentiation. J Invest Dermatol 123(2):305–312PubMedCrossRefGoogle Scholar
  36. 36.
    Schmuth M et al (2004) Peroxisome proliferator-activated receptor (PPAR)-beta/delta stimulates differentiation and lipid accumulation in keratinocytes. J Invest Dermatol 122(4):971–983PubMedCrossRefGoogle Scholar
  37. 37.
    Westergaard M et al (2001) Modulation of keratinocyte gene expression and differentiation by PPAR-selective ligands and tetradecylthioacetic acid. J Invest Dermatol 116(5):702–712PubMedCrossRefGoogle Scholar
  38. 38.
    Demerjian M et al (2006) Topical treatment with thiazolidinediones, activators of peroxisome proliferator-activated receptor-gamma, normalizes epidermal homeostasis in a murine hyperproliferative disease model. Exp Dermatol 15(3):154–160PubMedCrossRefGoogle Scholar
  39. 39.
    Ellis CN et al (2000) Troglitazone improves psoriasis and normalizes models of proliferative skin disease: ligands for peroxisome proliferator-activated receptor-gamma inhibit keratinocyte proliferation. Arch Dermatol 136(5):609–616PubMedCrossRefGoogle Scholar
  40. 40.
    Kim DJ et al (2006) PPARbeta/delta selectively induces differentiation and inhibits cell proliferation. Cell Death Differ 13(1):53–60PubMedCrossRefGoogle Scholar
  41. 41.
    Komuves LG et al (2000) Keratinocyte differentiation in hyperproliferative epidermis: topical application of PPARalpha activators restores tissue homeostasis. J Invest Dermatol 115(3):361–367PubMedCrossRefGoogle Scholar
  42. 42.
    Komuves LG et al (2000) Stimulation of PPARalpha promotes epidermal keratinocyte differentiation in vivo. J Invest Dermatol 115(3):353–360PubMedCrossRefGoogle Scholar
  43. 43.
    Lee SS et al (1995) Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 15(6):3012–3022PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Schmuth M et al (2002) Role of peroxisome proliferator-activated receptor alpha in epidermal development in utero. J Invest Dermatol 119(6):1298–1303PubMedCrossRefGoogle Scholar
  45. 45.
    Man MQ et al (2008) Deficiency of PPARbeta/delta in the epidermis results in defective cutaneous permeability barrier homeostasis and increased inflammation. J Invest Dermatol 128(2):370–377PubMedCrossRefGoogle Scholar
  46. 46.
    Demerjian M et al (2009) Activators of PPARs and LXR decrease the adverse effects of exogenous glucocorticoids on the epidermis. Exp Dermatol 18(7):643–649PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Michalik L et al (2001) Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice. J Cell Biol 154(4):799–814PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Icre G, Wahli W, Michalik L (2006) Functions of the peroxisome proliferator-activated receptor (PPAR) alpha and beta in skin homeostasis, epithelial repair, and morphogenesis. J Investig Dermatol Symp Proc 11(1):30–35PubMedCrossRefGoogle Scholar
  49. 49.
    Tan NS et al (2004) Essential role of Smad3 in the inhibition of inflammation-induced PPARbeta/delta expression. EMBO J 23(21):4211–4221PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Tan NS et al (2001) Critical roles of PPAR beta/delta in keratinocyte response to inflammation. Genes Dev 15(24):3263–3277PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Mirza RE et al (2015) Macrophage PPARgamma and impaired wound healing in type 2 diabetes. J Pathol 236(4):433–444PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Lucas T et al (2010) Differential roles of macrophages in diverse phases of skin repair. J Immunol 184(7):3964–3977PubMedCrossRefGoogle Scholar
  53. 53.
    Mirza R, DiPietro LA, Koh TJ (2009) Selective and specific macrophage ablation is detrimental to wound healing in mice. Am J Pathol 175(6):2454–2462PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Bannon P et al (2013) Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice. Dis Model Mech 6(6):1434–1447PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Khanna S et al (2010) Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS One 5(3):e9539PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Mirza R, Koh TJ (2011) Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice. Cytokine 56(2):256–264PubMedCrossRefGoogle Scholar
  57. 57.
    Hong C, Tontonoz P (2008) Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev 18(5):461–467PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Glass CK, Saijo K (2010) Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol 10(5):365–376PubMedCrossRefGoogle Scholar
  59. 59.
    Ricote M, Glass CK (2007) PPARs and molecular mechanisms of transrepression. Biochim Biophys Acta 1771(8):926–935PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Tyagi S et al (2011) The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases. J Adv Pharm Technol Res 2(4):236–240PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Jiang C, Ting AT, Seed B (1998) PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391(6662):82–86PubMedCrossRefGoogle Scholar
  62. 62.
    Bongartz T et al (2005) Treatment of active psoriatic arthritis with the PPARgamma ligand pioglitazone: an open-label pilot study. Rheumatology (Oxford) 44(1):126–129CrossRefGoogle Scholar
  63. 63.
    Mittal R et al (2009) Efficacy and safety of combination acitretin and pioglitazone therapy in patients with moderate to severe chronic plaque-type psoriasis: a randomized, double-blind, placebo-controlled clinical trial. Arch Dermatol 145(4):387–393PubMedCrossRefGoogle Scholar
  64. 64.
    Robertshaw H, Friedmann PS (2005) Pioglitazone: a promising therapy for psoriasis. Br J Dermatol 152(1):189–191PubMedCrossRefGoogle Scholar
  65. 65.
    Shafiq N et al (2005) Pilot trial: pioglitazone versus placebo in patients with plaque psoriasis (the P6). Int J Dermatol 44(4):328–333PubMedCrossRefGoogle Scholar
  66. 66.
    Behshad R, Cooper KD, Korman NJ (2008) A retrospective case series review of the peroxisome proliferator-activated receptor ligand rosiglitazone in the treatment of atopic dermatitis. Arch Dermatol 144(1):84–88PubMedCrossRefGoogle Scholar
  67. 67.
    Boguniewicz M, Leung DY (2011) Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 242(1):233–246PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Dahten A et al (2008) Systemic PPARgamma ligation inhibits allergic immune response in the skin. J Invest Dermatol 128(9):2211–2218PubMedCrossRefGoogle Scholar
  69. 69.
    Kawakami T et al (2009) Mast cells in atopic dermatitis. Curr Opin Immunol 21(6):666–678PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Tachibana M et al (2008) Activation of peroxisome proliferator-activated receptor gamma suppresses mast cell maturation involved in allergic diseases. Allergy 63(9):1136–1147PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Palmer CN et al (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38(4):441–446PubMedCrossRefGoogle Scholar
  72. 72.
    Wallmeyer L et al (2015) Stimulation of PPARalpha normalizes the skin lipid ratio and improves the skin barrier of normal and filaggrin deficient reconstructed skin. J Dermatol Sci 80(2):102–110PubMedCrossRefGoogle Scholar
  73. 73.
    Lee SE et al (2015) Pseudoceramide stimulates peroxisome proliferator-activated receptor-alpha expression in a murine model of atopic dermatitis: molecular basis underlying the anti-inflammatory effect and the preventive effect against steroid-induced barrier impairment. Arch Dermatol Res 307(9):781–792PubMedCrossRefGoogle Scholar
  74. 74.
    Romanowska M et al (2010) Activation of PPARbeta/delta causes a psoriasis-like skin disease in vivo. PLoS One 5(3):e9701PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Hack K et al (2012) Skin-targeted inhibition of PPAR beta/delta by selective antagonists to treat PPAR beta/delta-mediated psoriasis-like skin disease in vivo. PLoS One 7(5):e37097PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Kippenberger S et al (2001) Activators of peroxisome proliferator-activated receptors protect human skin from ultraviolet-B-light-induced inflammation. J Invest Dermatol 117(6):1430–1436PubMedCrossRefGoogle Scholar
  77. 77.
    Thuillier P et al (2000) Activators of peroxisome proliferator-activated receptor-alpha partially inhibit mouse skin tumor promotion. Mol Carcinog 29(3):134–142PubMedCrossRefGoogle Scholar
  78. 78.
    Kim DJ et al (2004) Peroxisome proliferator-activated receptor beta (delta)-dependent regulation of ubiquitin C expression contributes to attenuation of skin carcinogenesis. J Biol Chem 279(22):23719–23727PubMedCrossRefGoogle Scholar
  79. 79.
    Kim DJ et al (2005) Peroxisome proliferator-activated receptor-beta/delta inhibits epidermal cell proliferation by down-regulation of kinase activity. J Biol Chem 280(10):9519–9527PubMedCrossRefGoogle Scholar
  80. 80.
    Chen D, Auborn K (1999) Fish oil constituent docosahexa-enoic acid selectively inhibits growth of human papillomavirus immortalized keratinocytes. Carcinogenesis 20(2):249–254PubMedCrossRefGoogle Scholar
  81. 81.
    He G et al (2005) The effect of PPARgamma ligands on UV- or chemically-induced carcinogenesis in mouse skin. Mol Carcinog 43(4):198–206PubMedCrossRefGoogle Scholar
  82. 82.
    Nicol CJ et al (2004) PPARgamma influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis. Carcinogenesis 25(9):1747–1755PubMedCrossRefGoogle Scholar
  83. 83.
    Grabacka M et al (2006) Peroxisome proliferator-activated receptor alpha activation decreases metastatic potential of melanoma cells in vitro via down-regulation of Akt. Clin Cancer Res 12(10):3028–3036PubMedCrossRefGoogle Scholar
  84. 84.
    Liu Y et al (2006) Growth inhibition and differentiation induced by peroxisome proliferator activated receptor gamma ligand rosiglitazone in human melanoma cell line A375. Med Oncol 23(3):393–402PubMedCrossRefGoogle Scholar
  85. 85.
    Smith AG et al (2009) PPARgamma agonists attenuate proliferation and modulate Wnt/beta-catenin signalling in melanoma cells. Int J Biochem Cell Biol 41(4):844–852PubMedCrossRefGoogle Scholar
  86. 86.
    Grabacka M et al (2004) Inhibition of melanoma metastases by fenofibrate. Arch Dermatol Res 296(2):54–58PubMedCrossRefGoogle Scholar
  87. 87.
    Hanley K et al (1999) Fetal epidermal differentiation and barrier development In vivo is accelerated by nuclear hormone receptor activators. J Invest Dermatol 113(5):788–795PubMedCrossRefGoogle Scholar
  88. 88.
    Hanley K et al (2000) Oxysterols induce differentiation in human keratinocytes and increase Ap-1-dependent involucrin transcription. J Invest Dermatol 114(3):545–553PubMedCrossRefGoogle Scholar
  89. 89.
    Russell LE et al (2007) Characterization of liver X receptor expression and function in human skin and the pilosebaceous unit. Exp Dermatol 16(10):844–852PubMedCrossRefGoogle Scholar
  90. 90.
    Komuves LG et al (2002) Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-beta in murine epidermis. J Invest Dermatol 118(1):25–34PubMedCrossRefGoogle Scholar
  91. 91.
    Man MQ et al (2006) Basis for improved permeability barrier homeostasis induced by PPAR and LXR activators: liposensors stimulate lipid synthesis, lamellar body secretion, and post-secretory lipid processing. J Invest Dermatol 126(2):386–392PubMedCrossRefGoogle Scholar
  92. 92.
    Chang KC et al (2008) Liver X receptor is a therapeutic target for photoaging and chronological skin aging. Mol Endocrinol 22(11):2407–2419PubMedCrossRefGoogle Scholar
  93. 93.
    Fowler AJ et al (2003) Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptor-specific inhibition of inflammation and primary cytokine production. J Invest Dermatol 120(2):246–255PubMedCrossRefGoogle Scholar
  94. 94.
    Cork MJ et al (2006) New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol 118(1):3–21 (Quiz 22–3) Google Scholar
  95. 95.
    Ong PY et al (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 347(15):1151–1160PubMedCrossRefGoogle Scholar
  96. 96.
    Proksch E, Jensen JM, Elias PM (2003) Skin lipids and epidermal differentiation in atopic dermatitis. Clin Dermatol 21(2):134–144PubMedCrossRefGoogle Scholar
  97. 97.
    Sugarman JL et al (2003) The objective severity assessment of atopic dermatitis score: an objective measure using permeability barrier function and stratum corneum hydration with computer-assisted estimates for extent of disease. Arch Dermatol 139(11):1417–1422PubMedCrossRefGoogle Scholar
  98. 98.
    Hatano Y et al (2010) Murine atopic dermatitis responds to peroxisome proliferator-activated receptors alpha and beta/delta (but not gamma) and liver X receptor activators. J Allergy Clin Immunol 125(1):160–169 (e1–5) Google Scholar
  99. 99.
    Zhang W et al (2014) Liver X receptor activation induces apoptosis of melanoma cell through caspase pathway. Cancer Cell Int 14(1):16PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Pencheva N et al (2014) Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation. Cell 156(5):986–1001PubMedCrossRefGoogle Scholar
  101. 101.
    Wang Z et al (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423(6939):555–560PubMedCrossRefGoogle Scholar
  102. 102.
    Safe S et al (2016) Nuclear receptor 4A (NR4A) family—orphans no more. J Steroid Biochem Mol Biol 157:48–60PubMedCrossRefGoogle Scholar
  103. 103.
    Mohan HM et al (2012) Molecular pathways: the role of NR4A orphan nuclear receptors in cancer. Clin Cancer Res 18(12):3223–3228PubMedCrossRefGoogle Scholar
  104. 104.
    Ranhotra HS (2015) The NR4A orphan nuclear receptors: mediators in metabolism and diseases. J Recept Signal Transduct Res 35(2):184–188PubMedCrossRefGoogle Scholar
  105. 105.
    Newton RA et al (2005) Activation of the cAMP pathway by variant human MC1R alleles expressed in HEK and in melanoma cells. Peptides 26(10):1818–1824PubMedCrossRefGoogle Scholar
  106. 106.
    Smith AG et al (2008) Melanocortin-1 receptor signaling markedly induces the expression of the NR4A nuclear receptor subgroup in melanocytic cells. J Biol Chem 283(18):12564–12570PubMedCrossRefGoogle Scholar
  107. 107.
    de Leseleuc L, Denis F (2006) Nur77 forms novel nuclear structures upon DNA damage that cause transcriptional arrest. Exp Cell Res 312(9):1507–1513PubMedCrossRefGoogle Scholar
  108. 108.
    Jagirdar K et al (2013) The NR4A2 nuclear receptor is recruited to novel nuclear foci in response to UV irradiation and participates in nucleotide excision repair. PLoS One 8(11):e78075. doi: 10.1371/journal.pone.0078075 PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Malewicz M et al (2011) Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair. Genes Dev 25(19):2031–2040PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Malewicz M, Perlmann T (2014) Function of transcription factors at DNA lesions in DNA repair. Exp Cell Res 329(1):94–100PubMedCrossRefGoogle Scholar
  111. 111.
    Inamoto T et al (2008) 1,1-Bis(3′-indolyl)-1-(p-chlorophenyl)methane activates the orphan nuclear receptor Nurr1 and inhibits bladder cancer growth. Mol Cancer Ther 7(12):3825–3833PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Inamoto T et al (2010) Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer. Cancer 116(2):340–346PubMedCrossRefGoogle Scholar
  113. 113.
    Li X, Lee SO, Safe S (2012) Structure-dependent activation of NR4A2 (Nurr1) by 1,1-bis(3′-indolyl)-1-(aromatic)methane analogs in pancreatic cancer cells. Biochem Pharmacol 83(10):1445–1455PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Boakye CH et al (2013) Chemoprevention of skin cancer with 1,1-bis (3′-indolyl)-1-(aromatic) methane analog through induction of the orphan nuclear receptor, NR4A2 (Nurr1). PLoS One 8(8):e69519PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    O’Kane M et al (2008) Increased expression of the orphan nuclear receptor NURR1 in psoriasis and modulation following TNF-alpha inhibition. J Invest Dermatol 128(2):300–310PubMedCrossRefGoogle Scholar
  116. 116.
    Niu G et al (2015) Orphan nuclear receptor TR3/Nur77 improves wound healing by upregulating the expression of integrin beta4. FASEB J 29(1):131–140PubMedCrossRefGoogle Scholar
  117. 117.
    Palumbo-Zerr K et al (2015) Orphan nuclear receptor NR4A1 regulates transforming growth factor-beta signaling and fibrosis. Nat Med 21(2):150–158PubMedCrossRefGoogle Scholar
  118. 118.
    Smith AG et al (2011) Regulation of NR4A nuclear receptor expression by oncogenic BRAF in melanoma cells. Pigment Cell Melanoma Res 24(3):551–563PubMedCrossRefGoogle Scholar
  119. 119.
    Wong DJ, Ribas A (2016) Targeted therapy for melanoma. Cancer Treat Res 167:251–262PubMedCrossRefGoogle Scholar
  120. 120.
    Johannessen CM et al (2013) A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 504(7478):138–142PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Jetten AM (2009) Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal 7:e003PubMedPubMedCentralGoogle Scholar
  122. 122.
    Slominski A et al (2005) On the role of melatonin in skin physiology and pathology. Endocrine 27(2):137–148PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Steinmayr M et al (1998) Staggerer phenotype in retinoid-related orphan receptor alpha-deficient mice. Proc Natl Acad Sci USA 95(7):3960–3965PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Zhu Y et al (2006) RORA, a large common fragile site gene, is involved in cellular stress response. Oncogene 25(20):2901–2908PubMedCrossRefGoogle Scholar
  125. 125.
    Dai J et al (2013) The retinoid-related orphan receptor RORalpha promotes keratinocyte differentiation via FOXN1. PLoS One 8(7):e70392PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Hanyu O et al (2012) Cholesterol sulfate induces expression of the skin barrier protein filaggrin in normal human epidermal keratinocytes through induction of RORalpha. Biochem Biophys Res Commun 428(1):99–104PubMedCrossRefGoogle Scholar
  127. 127.
    Huh JR, Littman DR (2012) Small molecule inhibitors of RORgammat: targeting Th17 cells and other applications. Eur J Immunol 42(9):2232–2237PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Kallen JA et al (2002) X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure 10(12):1697–1707PubMedCrossRefGoogle Scholar
  129. 129.
    Solt LA, Burris TP (2012) Action of RORs and their ligands in (patho)physiology. Trends Endocrinol Metab 23(12):619–627PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Marciano DP et al (2014) The therapeutic potential of nuclear receptor modulators for treatment of metabolic disorders: PPARgamma, RORs, and Rev-erbs. Cell Metab 19(2):193–208PubMedCrossRefGoogle Scholar
  131. 131.
    Slominski AT et al (2014) The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions. J Steroid Biochem Mol Biol 144 Pt A:28–39Google Scholar
  132. 132.
    Skepner J et al (2014) Pharmacologic inhibition of RORgammat regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo. J Immunol 192(6):2564–2575PubMedCrossRefGoogle Scholar
  133. 133.
    Keijsers RR et al (2014) In vivo induction of cutaneous inflammation results in the accumulation of extracellular trap-forming neutrophils expressing RORgammat and IL-17. J Invest Dermatol 134(5):1276–1284PubMedCrossRefGoogle Scholar
  134. 134.
    Wang H, LeCluyse EL (2003) Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 42(15):1331–1357PubMedCrossRefGoogle Scholar
  135. 135.
    Elentner A et al (2015) Skin response to a carcinogen involves the xenobiotic receptor pregnane X receptor. Exp DermatolGoogle Scholar
  136. 136.
    Beyer C et al (2013) Activation of pregnane X receptor inhibits experimental dermal fibrosis. Ann Rheum Dis 72(4):621–625PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  1. 1.School of Biomedical SciencesUniversity of QueenslandBrisbaneAustralia
  2. 2.Dermatology Research Centre, School of MedicineUniversity of QueenslandBrisbaneAustralia
  3. 3.School of Biomedical Science, Institute of Health and Biomedical Innovation at the Translational Research InstituteQueensland University of TechnologyWoolloongabbaAustralia

Personalised recommendations