Vitamin D and the skin: Physiology and pathophysiology

Article

Abstract

The keratinocytes of the skin are unique in being not only the primary source of vitamin D for the body, but in possessing both the enzymatic machinery to metabolize the vitamin D produced to active metabolites (in particular 1,25(OH)2D) and the vitamin D receptor (VDR) that enables the keratinocytes to respond to the 1,25(OH)2D thus generated. Numerous functions of the skin are regulated by vitamin D and/or its receptor. These include inhibition of proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, regulation of the hair follicle cycle, and suppression of tumor formation. Regulation of these actions is exerted by a number of different coregulator complexes including the coactivators vitamin D receptor interacting protein (DRIP) complex also known as Mediator and the steroid receptor coactivator (SRC) family (of which SRC 2 and 3 are found in keratincytes), the inhibitor hairless (Hr), and β-catenin whose impact on VDR function is complex. Different coregulators appear to be involved in different VDR regulated functions. This review will examine the various functions of vitamin D and its receptor in the skin, and explore the mechanisms by which these functions are regulated.

Keywords

Vitamin D Epidermis Hair follicle Co-regulators Differentiation Carcinogenesis 

Notes

Acknowledgements

The author acknowledges the administrative assistance of Teresa Tong. The work discussed is primarily that done by a talented group researchers including Drs. Arnaud Teichert, Yuko Oda, Chia-Ling Tu, and Zhongjian Xie supported by the technical assistance of Hashem Elalieh and Vadim Bul. The work was supported by grants from the NIH RO1s AR050023, AR051930, PO1 AR39448, AICR 07A140, and a VA Merit Review.

References

  1. 1.
    Bikle DD, Pillai S. Vitamin D, calcium, and epidermal differentiation. Endocr Rev. 1993;14:3–19.PubMedGoogle Scholar
  2. 2.
    Tu CL, Chang W, Bikle DD. The extracellular calcium-sensing receptor is required for calcium- induced differentiation in human keratinocytes. J Biol Chem. 2001;276:41079–85.PubMedGoogle Scholar
  3. 3.
    Tu CL, Chang W, Bikle DD. Phospholipase cgamma1 is required for activation of store-operated channels in human keratinocytes. J Invest Dermatol. 2005;124:187–97.PubMedGoogle Scholar
  4. 4.
    Tu C, Chang W, Xie Z, Bikle D. Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human epidermal keratinocytes. J Biol Chem. 2008;283:3519–28.PubMedGoogle Scholar
  5. 5.
    Xie Z, Singleton PA, Bourguignon LY, Bikle DD. Calcium-induced human keratinocyte differentiation requires src- and fyn-mediated phosphatidylinositol 3-kinase-dependent activation of phospholipase C-gamma1. Mol Biol Cell. 2005;16:3236–46.PubMedGoogle Scholar
  6. 6.
    Xie Z, Bikle DD. The recruitment of phosphatidylinositol 3-kinase to the E-cadherin-catenin complex at the plasma membrane is required for calcium-induced phospholipase C-gamma1 activation and human keratinocyte differentiation. J Biol Chem. 2007;282:8695–703.PubMedGoogle Scholar
  7. 7.
    Xie Z, Chang SM, Pennypacker SD, Liao EY, Bikle DD. Phosphatidylinositol-4-phosphate 5-kinase 1alpha mediates extracellular calcium-induced keratinocyte differentiation. Mol Biol Cell. 2009;20:1695–704.PubMedGoogle Scholar
  8. 8.
    Yuspa SH, Kilkenny AE, Steinert PM, Roop DR. Expression of murine epidermal differentiation markers is tightly regulated by restricted extracellular calcium concentrations in vitro. J Cell Biol. 1989;109:1207–17.PubMedGoogle Scholar
  9. 9.
    Hohl D. Cornified cell envelope. Dermatologica. 1990;180:201–11.PubMedGoogle Scholar
  10. 10.
    Thacher SM, Rice RH. Keratinocyte-specific transglutaminase of cultured human epidermal cells: relation to cross-linked envelope formation and terminal differentiation. Cell. 1985;40:685–95.PubMedGoogle Scholar
  11. 11.
    Hennings H, Steinert P, Buxman MM. Calcium induction of transglutaminase and the formation of epsilon(gamma-glutamyl) lysine cross-links in cultured mouse epidermal cells. Biochem Biophys Res Commun. 1981;102:739–45.PubMedGoogle Scholar
  12. 12.
    Menon GK, Grayson S, Elias PM. Ionic calcium reservoirs in mammalian epidermis: ultrastructural localization by ion-capture cytochemistry. J Invest Dermatol. 1985;84:508–12.PubMedGoogle Scholar
  13. 13.
    Tu CL, Oda Y, Komuves L, Bikle DD. The role of the calcium-sensing receptor in epidermal differentiation. Cell Calcium. 2004;35:265–73.PubMedGoogle Scholar
  14. 14.
    Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, et al. Cloning and characterization of an extracellular Ca-2 + −sensing receptor from bovine parathyroid. Nature. 1993;366:575–80.PubMedGoogle Scholar
  15. 15.
    Oda Y, Tu CL, Pillai S, Bikle DD. The calcium sensing receptor and its alternatively spliced form in keratinocyte differentiation. J Biol Chem. 1998;273:23344–52.PubMedGoogle Scholar
  16. 16.
    Chang W, Tu C, Chen TH, Bikle D, Shoback D. The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci Signal. 2008;1:1–13.PubMedGoogle Scholar
  17. 17.
    Ratnam AV, Bikle DD, Cho JK. 1,25 dihydroxyvitamin D3 enhances the calcium response of keratinocytes. J Cell Physiol. 1999;178:188–96.PubMedGoogle Scholar
  18. 18.
    Xie Z, Bikle DD. Cloning of the human phospholipase C-gamma1 promoter and identification of a DR6-type vitamin D-responsive element. J Biol Chem. 1997;272:6573–7.PubMedGoogle Scholar
  19. 19.
    Xie Z, Bikle DD. Phospholipase C-gamma1 is required for calcium-induced keratinocyte differentiation. J Biol Chem. 1999;274:20421–4.PubMedGoogle Scholar
  20. 20.
    Xie Z, Bikle DD. Inhibition of 1,25-Dihydroxyvitamin-D-Induced keratinocyte differentiation by blocking the expression of phospholipase C-gamma1. J Invest Dermatol. 2001;117:1250–4.PubMedGoogle Scholar
  21. 21.
    Su MJ, Bikle DD, Mancianti ML, Pillai S. 1,25-Dihydroxyvitamin D3 potentiates the keratinocyte response to calcium. J Biol Chem. 1994;269:14723–9.PubMedGoogle Scholar
  22. 22.
    Ng DC, Shafaee S, Lee D, Bikle DD. Requirement of an AP-1 site in the calcium response region of the involucrin promoter. J Biol Chem. 2000;275:24080–8.PubMedGoogle Scholar
  23. 23.
    Bikle DD, Ng D, Oda Y, Hanley K, Feingold K, Xie Z. The vitamin D response element of the involucrin gene mediates its regulation by 1,25-dihydroxyvitamin D3. J Invest Dermatol. 2002;119:1109–13.PubMedGoogle Scholar
  24. 24.
    Pillai S, Bikle DD. Role of intracellular-free calcium in the cornified envelope formation of keratinocytes: differences in the mode of action of extracellular calcium and 1,25 dihydroxyvitamin D3. J Cell Physiol. 1991;146:94–100.PubMedGoogle Scholar
  25. 25.
    Bikle DD, Pillai S, Gee E. Squamous carcinoma cell lines produce 1,25 dihydroxyvitamin D, but fail to respond to its prodifferentiating effect. J Invest Dermatol. 1991;97:435–41.PubMedGoogle Scholar
  26. 26.
    Hosomi J, Hosoi J, Abe E, Suda T, Kuroki T. Regulation of terminal differentiation of cultured mouse epidermal cells by 1 alpha,25-dihydroxyvitamin D3. Endocrinology. 1983;113:1950–7.PubMedGoogle Scholar
  27. 27.
    Smith EL, Walworth NC, Holick MF. Effect of 1 alpha,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions. J Invest Dermatol. 1986;86:709–14.PubMedGoogle Scholar
  28. 28.
    McLane JA, Katz M, Abdelkader N. Effect of 1,25-dihydroxyvitamin D3 on human keratinocytes grown under different culture conditions. In Vitro Cell Dev Biol. 1990;26:379–87.PubMedGoogle Scholar
  29. 29.
    Hawker NP, Pennypacker SD, Chang SM, Bikle DD. Regulation of human epidermal keratinocyte differentiation by the vitamin D receptor and its coactivators DRIP205, SRC2, and SRC3. J Invest Dermatol. 2007;127:874.PubMedGoogle Scholar
  30. 30.
    Matsumoto K, Hashimoto K, Nishida Y, Hashiro M, Yoshikawa K. Growth-inhibitory effects of 1,25-dihydroxyvitamin D3 on normal human keratinocytes cultured in serum-free medium. Biochem Biophys Res Commun. 1990;166:916–23.PubMedGoogle Scholar
  31. 31.
    Bikle DD. The vitamin D receptor: a tumor suppressor in skin. Discov Med. 2011;11:7–17.PubMedGoogle Scholar
  32. 32.
    Oda Y, Uchida Y, Moradian S, Crumrine D, Elias P, Bikle D. Vitamin D receptor and coactivators SRC 2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation. J Invest Dermatol. 2009;129:1367–78.PubMedGoogle Scholar
  33. 33.
    Schauber J, Dorschner RA, Coda AB, Buchau AS, Liu PT, Kiken D, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest. 2007;117:803–11.PubMedGoogle Scholar
  34. 34.
    Schauber J, Dorschner RA, Yamasaki K, Brouha B, Gallo RL. Control of the innate epithelial antimicrobial response is cell-type specific and dependent on relevant microenvironmental stimuli. Immunology. 2006;118:509–19.PubMedGoogle Scholar
  35. 35.
    Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci USA. 1997;94:9831–5.PubMedGoogle Scholar
  36. 36.
    Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet. 1997;16:391–6.PubMedGoogle Scholar
  37. 37.
    Malloy PJ, Pike JW, Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev. 1999;20:156–88.PubMedGoogle Scholar
  38. 38.
    Xie Z, Komuves L, Yu QC, Elalieh H, Ng DC, Leary C, et al. Lack of the vitamin D receptor is associated with reduced epidermal differentiation and hair follicle growth. J Invest Dermatol. 2002;118:11–6.PubMedGoogle Scholar
  39. 39.
    Bikle DD, Elalieh H, Chang S, Xie Z, Sundberg JP. Development and progression of alopecia in the vitamin D receptor null mouse. J Cell Physiol. 2006;207:340–53.PubMedGoogle Scholar
  40. 40.
    Teichert A, Elalieh H, Bikle D. Disruption of the hedgehog signaling pathway contributes to the hair follicle cycling deficiency in Vdr knockout mice. J Cell Physiol. 2010;225:482–9.PubMedGoogle Scholar
  41. 41.
    Bikle DD, Chang S, Crumrine D, Elalieh H, Man MQ, Choi EH, et al. 25 Hydroxyvitamin D 1 alpha-hydroxylase is required for optimal epidermal differentiation and permeability barrier homeostasis. J Invest Dermatol. 2004;122:984–92.PubMedGoogle Scholar
  42. 42.
    Muehleisen B, Bikle D, Gallo RL. Interplay of vitamin D and innate immune responses affects bacterial skin infection. J Invest Dermatol. 2011;131:S1–S141. Abstracts #631.Google Scholar
  43. 43.
    Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, et al. Vitamin D receptor as an intestinal bile acid sensor. Science. 2002;296:1313–6.PubMedGoogle Scholar
  44. 44.
    Peric M, Koglin S, Dombrowski Y, Gross K, Bradac E, Ruzicka T, et al. VDR and MEK-ERK dependent induction of the antimicrobial peptide cathelicidin in keratinocytes by lithocholic acid. Mol Immunol. 2009;46:3183–7.PubMedGoogle Scholar
  45. 45.
    Zbytek B, Janjetovic Z, Tuckey RC, Zmijewski MA, Sweatman TW, Jones E, et al. 20-Hydroxyvitamin D3, a product of vitamin D3 hydroxylation by cytochrome P450scc, stimulates keratinocyte differentiation. J Invest Dermatol. 2008;128:2271–80.PubMedGoogle Scholar
  46. 46.
    Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab. 2001;86:888–94.PubMedGoogle Scholar
  47. 47.
    Milde P, Hauser U, Simon T, Mall G, Ernst V, Haussler MR, et al. Expression of 1,25-dihydroxyvitamin D3 receptors in normal and psoriatic skin. J Invest Dermatol. 1991;97:230–9.PubMedGoogle Scholar
  48. 48.
    Stumpf WE, Clark SA, Sar M, DeLuca HF. Topographical and developmental studies on target sites of 1,25 (OH)2 vitamin D3 in skin. Cell Tissue Res. 1984;238:489–96.PubMedGoogle Scholar
  49. 49.
    Oda Y, Sihlbom C, Chalkley RJ, Huang L, Rachez C, Chang CP, et al. Two distinct coactivators, DRIP/mediator and SRC/p160, are differentially involved in vitamin D receptor transactivation during keratinocyte differentiation. Mol Endocrinol. 2003;17:2329–39.PubMedGoogle Scholar
  50. 50.
    McKenna NJ, Lanz RB, O’Malley BW. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev. 1999;20:321–44.PubMedGoogle Scholar
  51. 51.
    Oda Y, Ishikawa MH, Hawker NP, Yun QC, Bikle DD. Differential role of two VDR coactivators, DRIP205 and SRC-3, in keratinocyte proliferation and differentiation. J Steroid Biochem Mol Biol. 2007;103:776–80.PubMedGoogle Scholar
  52. 52.
    Schauber J, Oda Y, Buchau AS, Steinmeyer A, Zugel U, Bikle DD, et al. Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D3. J Invest Dermatol. 2008;128:816–24.PubMedGoogle Scholar
  53. 53.
    Rachez C, Lemon BD, Suldan Z, Bromleigh V, Gamble M, Naar AM, et al. Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature. 1999;398:824–8.PubMedGoogle Scholar
  54. 54.
    Rachez C, Gamble M, Chang CP, Atkins GB, Lazar MA, Freedman LP. The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes. Mol Cell Biol. 2000;20:2718–26.PubMedGoogle Scholar
  55. 55.
    Leo C, Chen JD. The SRC family of nuclear receptor coactivators. Genes. 2000;245:1–11.Google Scholar
  56. 56.
    Teichert A, Arnold LA, Otieno S, Oda Y, Augustinaite I, Geistlinger TR, et al. Quantification of the vitamin D receptor-coregulator interaction. Biochemistry. 2009;48:1454–61.PubMedGoogle Scholar
  57. 57.
    Acevedo ML, Lee KC, Stender JD, Katzenellenbogen BS, Kraus WL. Selective recognition of distinct classes of coactivators by a ligand-inducible activation domain. Mol Cell. 2004;13:725–38.PubMedGoogle Scholar
  58. 58.
    Christakos S, Dhawan P, Liu Y, Peng X, Porta A. New insights into the mechanisms of vitamin D action. J Cell Biochem. 2003;88:695–705.PubMedGoogle Scholar
  59. 59.
    Rachez C, Freedman LP. Mechanisms of gene regulation by vitamin D(3) receptor: a network of coactivator interactions. Gene. 2000;246:9–21.PubMedGoogle Scholar
  60. 60.
    Carvallo L, Henriquez B, Paredes R, Olate J, Onate S, Van Wijnen AJ, et al. 1,25-dihydroxy vitamin D3-enhanced expression of the osteocalcin gene involves increased promoter occupancy of basal transcription regulators and gradual recruitment of the 1,25-dihydroxy vitamin D3 receptor-SRC-1 coactivator complex. J Cell Physiol. 2008;214:740–9.PubMedGoogle Scholar
  61. 61.
    Issa LL, Leong GM, Sutherland RL, Eisman JA. Vitamin D analogue-specific recruitment of vitamin D receptor coactivators. J Bone Miner Res. 2002;17:879–90.PubMedGoogle Scholar
  62. 62.
    Bouillon R, Verlinden L, Eelen G, De Clercq P, Vandewalle M, Mathieu C, et al. Mechanisms for the selective action of vitamin D analogs. J Steroid Biochem Mol Biol. 2005;97:21–30.PubMedGoogle Scholar
  63. 63.
    Maeda Y, Rachez C, Hawel IL, Byus CV, Freedman LP, Sladek FM. Polyamines modulate the interaction between nuclear receptors and vitamin D receptor-interacting protein 205. Mol Endocrinol. 2002;16:1502–10.PubMedGoogle Scholar
  64. 64.
    Peleg S, Ismail A, Uskokovic M, Avnur Z. Evidence for tissue- and cell-type selective activation of the vitamin D receptor by Ro-26-9228, a noncalcemic analog of vitamin D3. J Cell Biochem. 2003;88:267–73.PubMedGoogle Scholar
  65. 65.
    Schauber J, Oda Y, Buchau AS, Yun QC, Steinmeyer A, Zugel U, et al. Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-Dihydroxyvitamin D(3). J Invest Dermatol. 2008;128:816–24.PubMedGoogle Scholar
  66. 66.
    Bikle DD, Teichert A, Arnold LA, Uchida Y, Elias PM, Oda Y. Differential regulation of epidermal function by VDR coactivators. J Steroid Biochem Mol Biol. 2010;121:308–13.PubMedGoogle Scholar
  67. 67.
    Beaudoin III GM, Sisk JM, Coulombe PA, Thompson CC. Hairless triggers reactivation of hair growth by promoting Wnt signaling. Proc Natl Acad Sci USA. 2005;102:14653–8.PubMedGoogle Scholar
  68. 68.
    Djabali K, Aita VM, Christiano AM. Hairless is translocated to the nucleus via a novel bipartite nuclear localization signal and is associated with the nuclear matrix. J Cell Sci. 2001;114:367–76.PubMedGoogle Scholar
  69. 69.
    Liu L, Kim H, Casta A, Luke C, Kobayashi Y, Shapiro LS, et al. Hairless is a H3K9 histone demethylase. J Invest Dermatol. 2011;131:S1–S141. S169, #409.Google Scholar
  70. 70.
    Thompson CC, Bottcher MC. The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors. Proc Natl Acad Sci USA. 1997;94:8527–32.PubMedGoogle Scholar
  71. 71.
    Engelhard A, Christiano AM. The hairless promoter is differentially regulated by thyroid hormone in keratinocytes and neuroblastoma cells. Exp Dermatol. 2004;13:257–64.PubMedGoogle Scholar
  72. 72.
    Xie Z, Chang S, Oda Y, Bikle DD. Hairless suppresses vitamin D receptor transactivation in human keratinocytes. Endocrinology. 2006;147:314–23.PubMedGoogle Scholar
  73. 73.
    Hsieh JC, Sisk JM, Jurutka PW, Haussler CA, Slater SA, Haussler MR, et al. Physical and functional interaction between the vitamin D receptor and hairless corepressor, two proteins required for hair cycling. J Biol Chem. 2003;278:38665–74.PubMedGoogle Scholar
  74. 74.
    Zarach JM, Beaudoin 3rd GM, Coulombe PA, Thompson CC. The co-repressor hairless has a role in epithelial cell differentiation in the skin. Development. 2004;131:4189–200.PubMedGoogle Scholar
  75. 75.
    He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, et al. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509–12.PubMedGoogle Scholar
  76. 76.
    Bienz M. beta-Catenin: a pivot between cell adhesion and Wnt signalling. Curr Biol. 2005;15:R64–67.PubMedGoogle Scholar
  77. 77.
    Chan EF, Gat U, McNiff JM, Fuchs E. A common human skin tumour is caused by activating mutations in beta-catenin. Nat Genet. 1999;21:410–3.PubMedGoogle Scholar
  78. 78.
    Gat U, DasGupta R, Degenstein L, Fuchs E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell. 1998;95:605–14.PubMedGoogle Scholar
  79. 79.
    Xia J, Urabe K, Moroi Y, Koga T, Duan H, Li Y, et al. beta-Catenin mutation and its nuclear localization are confirmed to be frequent causes of Wnt signaling pathway activation in pilomatricomas. J Dermatol Sci. 2006;41:67–75.PubMedGoogle Scholar
  80. 80.
    Palmer HG, Gonzalez-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, et al. Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol. 2001;154:369–87.PubMedGoogle Scholar
  81. 81.
    Shah S, Hecht A, Pestell R, Byers SW. Trans-repression of beta-catenin activity by nuclear receptors. J Biol Chem. 2003;278:48137–45.PubMedGoogle Scholar
  82. 82.
    Teichert A, Elalieh H, Elias P, Welsh J, Bikle D. Over-expression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor null mice. J Invest Dermatol. (in press)2011.Google Scholar
  83. 83.
    Shah S, Islam MN, Dakshanamurthy S, Rizvi I, Rao M, Herrell R, et al. The molecular basis of vitamin D receptor and beta-catenin crossregulation. Mol Cell. 2006;21:799–809.PubMedGoogle Scholar
  84. 84.
    Palmer HG, Anjos-Afonso F, Carmeliet G, Takeda H, Watt FM. The vitamin D receptor is a Wnt Effector that controls hair follicle differentiation and specifies tumor type in adult epidermis. PLoS ONE. 2008;3:e1483.PubMedGoogle Scholar
  85. 85.
    Cianferotti L, Cox M, Skorija K, Demay MB. Vitamin D receptor is essential for normal keratinocyte stem cell function. Proc Natl Acad Sci USA. 2007;104:9428–33.PubMedGoogle Scholar
  86. 86.
    Shimizu H, Morgan BA. Wnt signaling through the beta-catenin pathway is sufficient to maintain, but not restore, anagen-phase characteristics of dermal papilla cells. J Invest Dermatol. 2004;122:239–45.PubMedGoogle Scholar
  87. 87.
    Kishimoto J, Burgeson RE, Morgan BA. Wnt signaling maintains the hair-inducing activity of the dermal papilla. Genes Dev. 2000;14:1181–5.PubMedGoogle Scholar
  88. 88.
    Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, et al. Capturing and profiling adult hair follicle stem cells. Nat Biotechnol. 2004;22:411–7.PubMedGoogle Scholar
  89. 89.
    Langbein L, Rogers MA, Praetzel S, Winter H, Schweizer J. K6irs1, K6irs2, K6irs3, and K6irs4 represent the inner-root-sheath-specific type II epithelial keratins of the human hair follicle. J Invest Dermatol. 2003;120:512–22.PubMedGoogle Scholar
  90. 90.
    Zhou P, Byrne C, Jacobs J, Fuchs E. Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate. Genes Dev. 1995;9:700–13.PubMedGoogle Scholar
  91. 91.
    Hochberg Z, Gilhar A, Haim S, Friedman-Birnbaum R, Levy J, Benderly A. Calcitriol-resistant rickets with alopecia. Arch Dermatol. 1985;121:646–7.PubMedGoogle Scholar
  92. 92.
    Marx SJ, Bliziotes MM, Nanes M. Analysis of the relation between alopecia and resistance to 1,25-dihydroxyvitamin D. Clin Endocrinol (Oxf). 1986;25:373–81.Google Scholar
  93. 93.
    Sakai Y, Demay MB. Evaluation of keratinocyte proliferation and differentiation in vitamin D receptor knockout mice. Endocrinology. 2000;141:2043–9.PubMedGoogle Scholar
  94. 94.
    Kong J, Li XJ, Gavin D, Jiang Y, Li YC. Targeted expression of human vitamin d receptor in the skin promotes the initiation of the postnatal hair follicle cycle and rescues the alopecia in vitamin D receptor null mice. J Invest Dermatol. 2002;118:631–8.PubMedGoogle Scholar
  95. 95.
    Chen CH, Sakai Y, Demay MB. Targeting expression of the human vitamin D receptor to the keratinocytes of vitamin D receptor null mice prevents alopecia. Endocrinology. 2001;142:5386–9.PubMedGoogle Scholar
  96. 96.
    Li YC, Amling M, Pirro AE, Priemel M, Meuse J, Baron R, et al. Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. Endocrinology. 1998;139:4391–6.PubMedGoogle Scholar
  97. 97.
    Teichert A, Elalieh H, Bikle D. Role of vitamin D receptor in hair follicle cycling through local expression. J Invest Dermatol. 2011;131:S1–S141. Abstract #446.Google Scholar
  98. 98.
    Panteleyev AA, Botchkareva NV, Sundberg JP, Christiano AM, Paus R. The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation. Am J Pathol. 1999;155:159–71.PubMedGoogle Scholar
  99. 99.
    Miller J, Djabali K, Chen T, Liu Y, Ioffreda M, Lyle S, et al. Atrichia caused by mutations in the vitamin D receptor gene is a phenocopy of generalized atrichia caused by mutations in the hairless gene. J Invest Dermatol. 2001;117:612–7.PubMedGoogle Scholar
  100. 100.
    Ahmad W, Faiyaz ul Haque M, Brancolini V, Tsou HC, ul Haque S, Lam H, et al. Alopecia universalis associated with a mutation in the human hairless gene. Science. 1998;279:720–4.PubMedGoogle Scholar
  101. 101.
    Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol. 2002;118:216–25.PubMedGoogle Scholar
  102. 102.
    Stenn KS, Paus R. Controls of hair follicle cycling. Physiol Rev. 2001;81:449–94.PubMedGoogle Scholar
  103. 103.
    Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell. 2001;105:533–45.PubMedGoogle Scholar
  104. 104.
    DasGupta R, Rhee H, Fuchs E. A developmental conundrum: a stabilized form of beta-catenin lacking the transcriptional activation domain triggers features of hair cell fate in epidermal cells and epidermal cell fate in hair follicle cells. J Cell Biol. 2002;158:331–44.PubMedGoogle Scholar
  105. 105.
    Chiang C, Swan RZ, Grachtchouk M, Bolinger M, Litingtung Y, Robertson EK, et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev Biol. 1999;205:1–9.PubMedGoogle Scholar
  106. 106.
    Reddy ST, Andl T, Lu MM, Morrisey EE, Millar SE. Expression of Frizzled genes in developing and postnatal hair follicles. J Invest Dermatol. 2004;123:275–82.PubMedGoogle Scholar
  107. 107.
    Luderer HF, Gori F, Demay MB. Lymphoid enhancer-binding factor-1 (LEF1) interacts the DNA-binding domain of the vitamin D receptor. J Biol Chem. 2011;286:18444–51.PubMedGoogle Scholar
  108. 108.
    Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin. 2001;51:15–36.PubMedGoogle Scholar
  109. 109.
    Freeman SE, Hacham H, Gange RW, Maytum DJ, Sutherland JC, Sutherland BM. Wavelength dependence of pyrimidine dimer formation in DNA of human skin irradiated in situ with ultraviolet light. Proc Natl Acad Sci USA. 1989;86:5605–9.PubMedGoogle Scholar
  110. 110.
    Hussein MR. Ultraviolet radiation and skin cancer: molecular mechanisms. J Cutan Pathol. 2005;32:191–205.PubMedGoogle Scholar
  111. 111.
    Daya-Grosjean L, Sarasin A. The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors. Mutat Res. 2005;571:43–56.PubMedGoogle Scholar
  112. 112.
    Ziegler A, Leffell DJ, Kunala S, Sharma HW, Gailani M, Simon JA, et al. Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. Proc Natl Acad Sci USA. 1993;90:4216–20.PubMedGoogle Scholar
  113. 113.
    Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, et al. Sunburn and p53 in the onset of skin cancer. Nature. 1994;372:773–6.PubMedGoogle Scholar
  114. 114.
    Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, et al. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA. 1991;88:10124–8.PubMedGoogle Scholar
  115. 115.
    Bito T, Ueda M, Ahmed NU, Nagano T, Ichihashi M. Cyclin D and retinoblastoma gene product expression in actinic keratosis and cutaneous squamous cell carcinoma in relation to p53 expression. J Cutan Pathol. 1995;22:427–34.PubMedGoogle Scholar
  116. 116.
    Reifenberger J, Wolter M, Knobbe CB, Kohler B, Schonicke A, Scharwachter C, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol. 2005;152:43–51.PubMedGoogle Scholar
  117. 117.
    Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668–71.PubMedGoogle Scholar
  118. 118.
    Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85:841–51.PubMedGoogle Scholar
  119. 119.
    Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas JM, et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol. 1998;110:885–8.PubMedGoogle Scholar
  120. 120.
    Aszterbaum M, Epstein J, Oro A, Douglas V, LeBoit PE, Scott MP, et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med. 1999;5:1285–91.PubMedGoogle Scholar
  121. 121.
    Ping XL, Ratner D, Zhang H, Wu XL, Zhang MJ, Chen FF, et al. PTCH mutations in squamous cell carcinoma of the skin. J Invest Dermatol. 2001;116:614–6.PubMedGoogle Scholar
  122. 122.
    Grachtchouk M, Pero J, Yang SH, Ermilov AN, Michael LE, Wang A, et al. Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations. J Clin Invest. 2011;121:1768–81.PubMedGoogle Scholar
  123. 123.
    Zinser GM, Sundberg JP, Welsh J. Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis. Carcinogenesis. 2002;23:2103–9.PubMedGoogle Scholar
  124. 124.
    Indra AK, Castaneda E, Antal MC, Jiang M, Messaddeq N, Meng X, Loehr CV, Gariglio P, Kato S, Wahli W, Desvergne B, Metzger D, Chambon P. Malignant transformation of DMBA/TPA-Induced papillomas and nevi in the skin of mice selectively lacking retinoid-X-receptor alpha in epidermal keratinocytes. J Invest Dermatol. 2007.Google Scholar
  125. 125.
    Ellison TI, Smith MK, Gilliam AC, Macdonald PN. Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-Induced tumorigenesis. J Invest Dermatol. 2008;128:2508–17.PubMedGoogle Scholar
  126. 126.
    Dixon KM, Deo SS, Wong G, Slater M, Norman AW, Bishop JE, et al. Skin cancer prevention: a possible role of 1,25dihydroxyvitamin D3 and its analogs. J Steroid Biochem Mol Biol. 2005;97:137–43.PubMedGoogle Scholar
  127. 127.
    Gupta R, Dixon KM, Deo SS, Holliday CJ, Slater M, Halliday GM, et al. Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products. J Invest Dermatol. 2007;127:707–15.PubMedGoogle Scholar
  128. 128.
    De Haes P, Garmyn M, Degreef H, Vantieghem K, Bouillon R, Segaert S. 1,25-Dihydroxyvitamin D3 inhibits ultraviolet B-induced apoptosis, Jun kinase activation, and interleukin-6 production in primary human keratinocytes. J Cell Biochem. 2003;89:663–73.PubMedGoogle Scholar
  129. 129.
    Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Ikram MS, et al. The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells. Oncogene. 2004;23:1263–74.PubMedGoogle Scholar
  130. 130.
    Barnfield PC, Zhang X, Thanabalasingham V, Yoshida M, Hui CC. Negative regulation of Gli1 and Gli2 activator function by suppressor of fused through multiple mechanisms. Differentiation. 2005;73:397–405.PubMedGoogle Scholar
  131. 131.
    Wakabayashi Y, Mao JH, Brown K, Girardi M, Balmain A. Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature. 2007;445:761–5.PubMedGoogle Scholar
  132. 132.
    Bijlsma MF, Spek CA, Zivkovic D, van de Water S, Rezaee F, Peppelenbosch MP. Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol. 2006;4:e232.PubMedGoogle Scholar
  133. 133.
    Tang JY, Xiao TZ, Oda Y, Chang KS, Shpall E, Wu A, et al. Vitamin D3 inhibits hedgehog signaling and proliferation in murine Basal cell carcinomas. Canc Prev Res (Philadelphia, Pa). 2011;4:744–51.Google Scholar
  134. 134.
    Svard J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergstrom A, et al. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell. 2006;10:187–97.PubMedGoogle Scholar
  135. 135.
    Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Philpott MP, et al. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 2004;64:7724–31.PubMedGoogle Scholar
  136. 136.
    Regl G, Neill GW, Eichberger T, Kasper M, Ikram MS, Koller J, et al. Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma. Oncogene. 2002;21:5529–39.PubMedGoogle Scholar
  137. 137.
    Grachtchouk M, Mo R, Yu S, Zhang X, Sasaki H, Hui CC, et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet. 2000;24:216–7.PubMedGoogle Scholar
  138. 138.
    Nilsson M, Unden AB, Krause D, Malmqwist U, Raza K, Zaphiropoulos PG, et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci USA. 2000;97:3438–43.PubMedGoogle Scholar
  139. 139.
    Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein Jr EH, Scott MP. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science. 1997;276:817–21.PubMedGoogle Scholar
  140. 140.
    Fan H, Oro AE, Scott MP, Khavari PA. Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog. Nat Med. 1997;3:788–92.PubMedGoogle Scholar
  141. 141.
    Tojo M, Mori T, Kiyosawa H, Honma Y, Tanno Y, Kanazawa KY, et al. Expression of sonic hedgehog signal transducers, patched and smoothened, in human basal cell carcinoma. Pathol Int. 1999;49:687–94.PubMedGoogle Scholar
  142. 142.
    Bonifas JM, Pennypacker S, Chuang PT, McMahon AP, Williams M, Rosenthal A, et al. Activation of expression of hedgehog target genes in basal cell carcinomas. J Invest Dermatol. 2001;116:739–42.PubMedGoogle Scholar
  143. 143.
    Eichberger T, Regl G, Ikram MS, Neill GW, Philpott MP, Aberger F, et al. FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma. J Invest Dermatol. 2004;122:1180–7.PubMedGoogle Scholar
  144. 144.
    Wang TT, Tavera-Mendoza LE, Laperriere D, Libby E, MacLeod NB, Nagai Y, et al. Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005;19:2685–95.PubMedGoogle Scholar
  145. 145.
    Saldanha G, Ghura V, Potter L, Fletcher A. Nuclear beta-catenin in basal cell carcinoma correlates with increased proliferation. Br J Dermatol. 2004;151:157–64.PubMedGoogle Scholar
  146. 146.
    Iwatsuki K, Liu HX, Gronder A, Singer MA, Lane TF, Grosschedl R, et al. Wnt signaling interacts with Shh to regulate taste papilla development. Proc Natl Acad Sci USA. 2007;104:2253–8.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Veterans Affairs Medical Center/University of California, San FranciscoSan FranciscoUSA

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