Regulation of Keratinocyte Differentiation by Vitamin D and Its Relationship to Squamous Cell Carcinoma



Vitamin D is a fat-soluble steroid hormone originally described as ­contributing to the maintenance of normal levels of calcium and phosphorus in the bloodstream. Strictly speaking, it is not a vitamin because human skin can manufacture it, but it is referred to as one for historical reasons. Vitamin D aids in the intestinal absorption of calcium, helping to form and maintain bone mineralization in concert with a number of other vitamins, minerals and hormones. Thus, vitamin D prevents rickets in children and osteomalacia in adults–skeletal diseases that result in defects that weaken bones.

Recent investigations have shown that vitamin D also functions as regulator of cellular growth and differentiation in various tissues, including the skin. The mechanisms by which 1,25 dihydroxyvitamin D3 (1,25(OH)2D3 or calcitriol), the active vitamin D metabolite, alters keratinocyte differentiation are multiple and overlap with the mechanisms by which calcium regulates keratinocyte differentiation. The antiproliferative, prodifferentiating effects of 1,25(OH)2D3 raise the hope that it may prevent malignant transformation of keratinocytes just as it appears to do in many other tissues. In particular, vitamin D has been evaluated for its potential anticancer activity because of the presence of vitamin D receptor (VDR) in most normal and malignant cells including basal and squamous-cell carcinomas and melanomas, and the susceptibility of VDR null mice to develop skin tumors. Physiological and pharmacological actions of 1,25(OH)2D3 in various systems have indicated potential applications of VDR ligands in inflammation, cancer and ­autoimmune disorders. As such, a better understanding of the metabolism and mechanism of action of vitamin D in the skin has opened up new perspectives for therapeutic application of vitamin D analogs in a number of skin diseases including the prevention of malignancy.


Stratum Corneum Lamellar Body Keratinocyte Differentiation Epidermal Differentiation Steroid Receptor Coactivator 
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  1. Belandia B, Parker MG (2003) Nuclear receptors: a rendezvous for chromatin remodeling factors. Cell 114:277–280PubMedCrossRefGoogle Scholar
  2. Berridge MJ (1993) Inositol trisphosphate and calcium signalling. Nature 361:315–325PubMedCrossRefGoogle Scholar
  3. Bikle D, Nemanic M, Whitney J, Elias P (1986a) Neonatal human foreskin keratinocytes produce 1, 25-dihydroxyvitamin D3. Biochemistry 25:1545–1548PubMedCrossRefGoogle Scholar
  4. Bikle DD, Nemanic MK, Gee E, Elias P (1986b) 1, 25-Dihydroxyvitamin D3 production by human keratinocytes. Kinetics and regulation. J Clin Invest 78:557–566PubMedCrossRefGoogle Scholar
  5. Bikle DD, Pillai S, Gee E, Hincenbergs M (1989) Regulation of 1, 25-dihydroxyvitamin D production in human keratinocytes by interferon-gamma. Endocrinology 124:655–660PubMedCrossRefGoogle Scholar
  6. Bikle DD, Pillai S, Gee E (1991a) Squamous carcinoma cell lines produce 1, 25 dihydroxyvitamin D, but fail to respond to its prodifferentiating effect. J Invest Dermatol 97:435–441PubMedCrossRefGoogle Scholar
  7. Bikle DD, Pillai S, Gee E, Hincenbergs M (1991b) Tumor necrosis factor-alpha regulation of 1, 25-dihydroxyvitamin D production by human keratinocytes. Endocrinology 129:33–38PubMedCrossRefGoogle Scholar
  8. Bikle DD, Halloran BP, Riviere JE (1994) Production of 1, 25 dihydroxyvitamin D3 by perfused pig skin. J Invest Dermatol 102:796–798PubMedCrossRefGoogle Scholar
  9. Bikle DD, Ratnam A, Mauro T, Harris J, Pillai S (1996) Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor. J Clin Invest 97:1085–1093PubMedCrossRefGoogle Scholar
  10. Bikle DD, Ng D, Oda Y, Hanley K, Feingold K, Xie Z (2002) The vitamin D response element of the involucrin gene mediates its regulation by 1, 25-dihydroxyvitamin D3. J Invest Dermatol 119:1109–1113PubMedCrossRefGoogle Scholar
  11. Bikle DD, Tu CL, Xie Z, Oda Y (2003) Vitamin D regulated keratinocyte differentiation: role of coactivators. J Cell Biochem 88:290–295PubMedCrossRefGoogle Scholar
  12. Bikle DD, Chang S, Crumrine D, Elalieh H, Man MQ, Choi EH, Dardenne O, Xie Z, Arnaud RS, Feingold K, Elias PM (2004) 25 Hydroxyvitamin D 1 alpha-hydroxylase is required for optimal epidermal differentiation and permeability barrier homeostasis. J Invest Dermatol 122:984–992PubMedCrossRefGoogle Scholar
  13. Bittiner B, Bleehen SS, MacNeil S (1991) 1 alpha, 25(OH)2 vitamin D3 increases intracellular calcium in human keratinocytes. Br J Dermatol 124:230–235PubMedCrossRefGoogle Scholar
  14. Bollag WB, Ducote J, Harmon CS (1995) Biphasic effect of 1, 25-dihydroxyvitamin D3 on ­primary mouse epidermal keratinocyte proliferation. J Cell Physiol 163:248–256PubMedCrossRefGoogle Scholar
  15. Bostick RM, Potter JD, Sellers TA, McKenzie DR, Kushi LH, Folsom AR (1993) Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. The Iowa Women’s Health Study. Am J Epidemiol 137:1302–1317PubMedGoogle Scholar
  16. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC (1993) Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 366:575–580PubMedCrossRefGoogle Scholar
  17. Calautti E, Missero C, Stein PL, Ezzell RM, Dotto GP (1995) fyn tyrosine kinase is involved in keratinocyte differentiation control. Genes Dev 9:2279–2291PubMedCrossRefGoogle Scholar
  18. Calautti E, Cabodi S, Stein PL, Hatzfeld M, Kedersha N, Paolo Dotto G (1998) Tyrosine phosphorylation and src family kinases control keratinocyte cell-cell adhesion. J Cell Biol 141:1449–1465PubMedCrossRefGoogle Scholar
  19. Carlberg C, Polly P (1998) Gene regulation by vitamin D3. Crit Rev Eukaryot Gene Expr 8:19–42PubMedGoogle Scholar
  20. Carpenter G, Ji Q (1999) Phospholipase C-gamma as a signal-transducing element. Exp Cell Res 253:15–24PubMedCrossRefGoogle Scholar
  21. Chen JD, Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377:454–457PubMedCrossRefGoogle Scholar
  22. Cichon S, Anker M, Vogt IR, Rohleder H, Putzstuck M, Hillmer A, Farooq SA, Al-Dhafri KS, Ahmad M, Haque S, Rietschel M, Propping P, Kruse R, Nothen MM (1998) Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia. Hum Mol Genet 7:1671–1679PubMedCrossRefGoogle Scholar
  23. Colston K, Colston MJ, Feldman D (1981) 1, 25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology 108:1083–1086PubMedCrossRefGoogle Scholar
  24. Dale BA, Resing KA, Lonsdale-Eccles JD (1985) Filaggrin: a keratin filament associated protein. Ann NY Acad Sci 455:330–342PubMedCrossRefGoogle Scholar
  25. Eichner R, Sun TT, Aebi U (1986) The role of keratin subfamilies and keratin pairs in the formation of human epidermal intermediate filaments. J Cell Biol 102:1767–1777PubMedCrossRefGoogle Scholar
  26. Eisman JA, Martin TJ, MacIntyre I, Moseley JM (1979) 1, 25-dihydroxyvitamin-D-receptor in breast cancer cells. Lancet 2:1335–1336PubMedCrossRefGoogle Scholar
  27. Elias PM, Menon GK, Grayson S, Brown BE (1988) Membrane structural alterations in murine stratum corneum: relationship to the localization of polar lipids and phospholipases. J Invest Dermatol 91:3–10PubMedCrossRefGoogle Scholar
  28. Elias PM, Ahn SK, Denda M, Brown BE, Crumrine D, Kimutai LK, Komuves L, Lee SH, Feingold KR (2002) Modulations in epidermal calcium regulate the expression of differentiation-specific markers. J Invest Dermatol 119:1128–1136PubMedCrossRefGoogle Scholar
  29. Ellison TI, Eckert RL, MacDonald PN (2007) Evidence for 1, 25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes. J Biol Chem 282:10953–10962PubMedCrossRefGoogle Scholar
  30. Ellison TI, Smith MK, Gilliam AC, MacDonald PN (2008) Inactivation of the Vitamin D Receptor Enhances Susceptibility of Murine Skin to UV-Induced Tumorigenesis. J Invest Dermatol 128:2508–2571PubMedCrossRefGoogle Scholar
  31. Feng W, Ribeiro R, Wagner R, Nguyen H, Apriletti J, Fletterick R, Baxter J, Kushner P, West B (1998) Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science 280:1747–1749PubMedCrossRefGoogle Scholar
  32. Fu GK, Lin D, Zhang MY, Bikle DD, Shackleton CH, Miller WL, Portale AA (1997) Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol Endocrinol 11:1961–1970PubMedCrossRefGoogle Scholar
  33. Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O (1985) Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet 1:307–309PubMedCrossRefGoogle Scholar
  34. Garland FC, Garland CF, Gorham ED, Young JF (1990) Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 19:614–622PubMedCrossRefGoogle Scholar
  35. Garrett JE, Capuano IV, Hammerland LG, Hung BC, Brown EM, Hebert SC, Nemeth EF, Fuller F (1995) Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs. J Biol Chem 270:12919–12925PubMedCrossRefGoogle Scholar
  36. Gniadecki R (1996) Stimulation versus inhibition of keratinocyte growth by 1, 25-Dihydroxyvitamin D3: dependence on cell culture conditions. J Invest Dermatol 106:510–516PubMedCrossRefGoogle Scholar
  37. Guo M, Kim L, Akiyama S, Gralnick H, Yamada K, Grinnell F (1991) Altered processing of integrin receptors during keratinocyte activation. Exp Cell Res 195:315–322PubMedCrossRefGoogle Scholar
  38. Hanchette CL, Schwartz GG (1992) Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation. Cancer 70:2861–2869PubMedCrossRefGoogle Scholar
  39. Hashiro M, Matsumoto K, Hashimoto K, Yoshikawa K (1991) Stimulation of fibronectin secretion in cultured human keratinocytes by transforming growth factor-beta not by other growth inhibitory substances. J Dermatol 18:252–257PubMedGoogle Scholar
  40. Hawker NP, Pennypacker SD, Chang SM, Bikle DD (2007) Regulation of human epidermal keratinocyte differentiation by the vitamin D receptor and its coactivators DRIP205, SRC2, and SRC3. J Invest Dermatol 127:874–880PubMedCrossRefGoogle Scholar
  41. Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J, Yang WM, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG (1997) A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387:43–48PubMedCrossRefGoogle Scholar
  42. Hennings H, Holbrook KA (1983) Calcium regulation of cell-cell contact and differentiation of epidermal cells in culture. An ultrastructural study. Exp Cell Res 143:127–142PubMedCrossRefGoogle Scholar
  43. Hennings H, Michael D, Cheng C, Steinert P, Holbrook K, Yuspa SH (1980) Calcium regulation of growth and differentiation of mouse epidermal cells in culture. Cell 19:245–54PubMedCrossRefGoogle Scholar
  44. Hohl D (1990) Cornified cell envelope. Dermatologica 180:201–211PubMedCrossRefGoogle Scholar
  45. Hohl D, Lichti U, Breitkreutz D, Steinert PM, Roop DR (1991) Transcription of the human ­loricrin gene in vitro is induced by calcium and cell density and suppressed by retinoic acid. J Invest Dermatol 96:414–418PubMedCrossRefGoogle Scholar
  46. Holick MF (2004) Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 79:362–371PubMedGoogle Scholar
  47. Holleran WM, Takagi Y, Uchida Y (2006) Epidermal sphingolipids: metabolism, function, and roles in skin disorders. FEBS Lett 580:5456–5466PubMedCrossRefGoogle Scholar
  48. Hong H, Kohli K, Trivedi A, Johnson D, Stallcup M (1996) GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc Natl Acad Sci USA 93:4948–4952PubMedCrossRefGoogle Scholar
  49. Horiuchi N, Clemens TL, Schiller AL, Holick MF (1985) Detection and developmental changes of the 1, 25-(OH)2–D3 receptor concentration in mouse skin and intestine. J Invest Dermatol 84:461–464PubMedCrossRefGoogle Scholar
  50. Hosomi J, Hosoi J, Abe T, Suda T, Kuroki T (1983) Regulation of terminal differentiation of cultured mouse epidermal cells by 1 alpha, 25-dihydroxyvitamin D3. Endocrinology 113:1950–1957PubMedCrossRefGoogle Scholar
  51. Hsieh JC, Sisk JM, Jurutka PW, Haussler CA, Slater SA, Haussler MR, Thompson CC (2003) Physical and functional interaction between the vitamin D receptor and hairless corepressor, two proteins required for hair cycling. J Biol Chem 278:38665–38674PubMedCrossRefGoogle Scholar
  52. Huff CA, Yuspa SH, Rosenthal D (1993) Identification of control elements 3′ to the human keratin 1 gene that regulate cell type and differentiation-specific expression. J Biol Chem 268:377–384PubMedGoogle Scholar
  53. Hunter DJ, Colditz GA, Stampfer MJ, Rosner B, Willett WC, Speizer FE (1992) Diet and risk of basal cell carcinoma of the skin in a prospective cohort of women. Ann Epidemiol 2:231–239PubMedCrossRefGoogle Scholar
  54. 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 (2007) 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 127:1250–1260PubMedCrossRefGoogle Scholar
  55. Itin PH, Pittelkow MR, Kumar R (1994) Effects of vitamin D metabolites on proliferation and differentiation of cultured human epidermal keratinocytes grown in serum-free or defined culture medium. Endocrinology 135:1793–1798PubMedCrossRefGoogle Scholar
  56. Jaken S, Yuspa SH (1988) Early signals for keratinocyte differentiation: role of Ca2 + -mediated inositol lipid metabolism in normal and neoplastic epidermal cells. Carcinogenesis 9:1033–1038PubMedCrossRefGoogle Scholar
  57. Kamradt J, Rafi L, Mitschele T, Meineke V, Gartner BC, Wolfgang T, Holick MF, Reichrath J (2003) Analysis of the vitamin D system in cutaneous malignancies. Recent Results Cancer Res 164:259–269PubMedGoogle Scholar
  58. Kearney J, Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Wing A, Kampman E, Willett WC (1996) Calcium, vitamin D, and dairy foods and the occurrence of colon cancer in men. Am J Epidemiol 143:907–917PubMedGoogle Scholar
  59. Kim HJ, Abdelkader N, Katz M, McLane JA (1992) 1, 25-Dihydroxy-vitamin-D3 enhances antiproliferative effect and transcription of TGF-beta1 on human keratinocytes in culture. J Cell Physiol 151:579–587PubMedCrossRefGoogle Scholar
  60. Kira M, Kobayashi T, Yoshikawa K (2003) Vitamin D and the skin. J Dermatol 30:429–37PubMedGoogle Scholar
  61. Koli K, Keski-Oja J (1993) Vitamin D3 and calcipotriol enhance the secretion of transforming growth factor-beta 1 and -beta 2 in cultured murine keratinocytes. Growth Factors 8:153–163PubMedCrossRefGoogle Scholar
  62. Kremer R, Karaplis AC, Henderson J, Gulliver W, Banville D, Hendy GN, Goltzman D (1991) Regulation of parathyroid hormone-like peptide in cultured normal human keratinocytes. Effect of growth factors and 1, 25 dihydroxyvitamin D3 on gene expression and secretion. J Clin Invest 87:884–893PubMedCrossRefGoogle Scholar
  63. Kurokawa R, Soderstrom M, Horlein A, Halachmi S, Brown M, Rosenfeld M, Glass C (1995) Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature 377:451–454PubMedCrossRefGoogle Scholar
  64. Lathers DM, Clark JI, Achille NJ, Young MR (2004) Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3. Cancer Immunol Immunother 53:422–430PubMedCrossRefGoogle Scholar
  65. Lee E, Yuspa SH (1991) Aluminum fluoride stimulates inositol phosphate metabolism and inhibits expression of differentiation markers in mouse keratinocytes. J Cell Physiol 148:106–115PubMedCrossRefGoogle Scholar
  66. Lehmann B, Tiebel O, Meurer M (1999) Expression of vitamin D3 25-hydroxylase (CYP27) mRNA after induction by vitamin D3 or UVB radiation in keratinocytes of human skin equivalents–a preliminary study. Arch Dermatol Res 291:507–510PubMedCrossRefGoogle Scholar
  67. Lehmann B, Genehr T, Knuschke P, Pietzsch J, Meurer M (2001) UVB-induced conversion of 7-dehydrocholesterol to 1alpha, 25-dihydroxyvitamin D3 in an in vitro human skin equivalent model. J Invest Dermatol 117:1179–1185PubMedCrossRefGoogle Scholar
  68. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, Demay MB (1997) Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci USA 94:9831–9835PubMedCrossRefGoogle Scholar
  69. MacLaughlin JA, Cantley LC, Holick MF (1990) 1, 25(OH)2D3 increases calcium and phosphatidylinositol metabolism in differentiating cultured human keratinocytes. J Nutr Biochem 1:81–87PubMedCrossRefGoogle Scholar
  70. Marchisio P, Bondanza S, Cremona O, Cancedda R, De Luca M (1991) Polarized expression of integrin receptors (alpha 6 beta 4, alpha 2 beta 1, alpha 3 beta 1, and alpha v beta 5) and their relationship with the cytoskeleton and basement membrane matrix in cultured human keratinocytes. J Cell Biol 112:761–773PubMedCrossRefGoogle Scholar
  71. Masumoto O, Ohyama Y, Okuda K (1988) Purification and characterization of vitamin D 25-hydroxylase from rat liver mitochondria. J Biol Chem 263:14256–14260PubMedGoogle Scholar
  72. Matsumoto K, Hashimoto K, Nishida Y, Hashiro M, Yoshikawa K (1990) Growth-inhibitory effects of 1, 25-dihydroxyvitamin D3 on normal human keratinocytes cultured in serum-free medium. Biochem Biophys Res Commun 166:916–923PubMedCrossRefGoogle Scholar
  73. Matsumoto K, Azuma Y, Kiyoki M, Okumura H, Hashimoto K, Yoshikawa K (1991) Involvement of endogenously produced 1, 25-dihydroxyvitamin D-3 in the growth and differentiation of human keratinocytes. Biochim Biophys Acta 1092:311–318PubMedCrossRefGoogle Scholar
  74. Mauro T, Bench G, Sidderas-Haddad E, Feingold K, Elias P, Cullander C (1998) Acute barrier perturbation abolishes the Ca2+ and K + gradients in murine epidermis: quantitative measurement using PIXE. J Invest Dermatol 111:1198–1201PubMedCrossRefGoogle Scholar
  75. McLane JA, Katz M, Abdelkader N (1990) Effect of 1, 25-dihydroxyvitamin D3 on human keratinocytes grown under different culture conditions. In Vitro Cell Dev Biol 26:379–387PubMedCrossRefGoogle Scholar
  76. Mehrel T, Hohl D, Rothnagel JA, Longley MA, Bundman D, Cheng C, Lichti U, Bisher ME, Steven AC, Steinert PM (1990) Identification of a major keratinocyte cell envelope protein, loricrin. Cell 61:1103–1112PubMedCrossRefGoogle Scholar
  77. Menon GK, Grayson S, Elias PM (1985) Ionic calcium reservoirs in mammalian epidermis: ultrastructural localization by ion-capture cytochemistry. J Invest Dermatol 84:508–512PubMedCrossRefGoogle Scholar
  78. Merke J, Schwittay D, Furstenberger G, Gross M, Marks F, Ritz E (1985) Demonstration and characterization of 1, 25-dihydroxyvitamin D3 receptors in basal cells of epidermis of neonatal and adult mice. Calcif Tissue Int 37:257–267PubMedCrossRefGoogle Scholar
  79. Milde P, Hauser U, Simon T, Mall G, Ernst V, Haussler MR, Frosch P, Rauterberg EW (1991) Expression of 1, 25-dihydroxyvitamin D3 receptors in normal and psoriatic skin. J Invest Dermatol 97:230–29PubMedCrossRefGoogle Scholar
  80. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R (1982) The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31:11–24PubMedCrossRefGoogle Scholar
  81. Moras D, Gronemeyer H (1998) The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 10:384–391PubMedCrossRefGoogle Scholar
  82. Morhenn VB, Wood GS (1988) Gamma interferon-induced expression of class II major histocompatibility complex antigens by human keratinocytes. Effects of conditions of culture. Ann NY Acad Sci 548:321–330PubMedCrossRefGoogle Scholar
  83. Moscat J, Fleming TP, Molloy CJ, Lopez-Barahona M, Aaronson SA (1989) The calcium signal for Balb/MK keratinocyte terminal differentiation induces sustained alterations in phosphoinositide metabolism without detectable protein kinase C activation. J Biol Chem 264:11228–11235PubMedGoogle Scholar
  84. Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, Evans RM (1997) Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89:373–380PubMedCrossRefGoogle Scholar
  85. Ng DC, Su MJ, Kim R, Bikle DD (1996) Regulation of involucrin gene expression by calcium in normal human keratinocytes. Front Biosci 1:a16–24PubMedGoogle Scholar
  86. Oda Y, Tu CL, Chang W, Crumrine D, Komuves L, Mauro T, Elias PM, Bikle DD (2000) The calcium sensing receptor and its alternatively spliced form in murine epidermal differentiation. J Biol Chem 275:1183–1190PubMedCrossRefGoogle Scholar
  87. Oda Y, Sihlbom C, Chalkley RJ, Huang L, Rachez C, Chang CP, Burlingame AL, Freedman LP, Bikle DD (2003) Two distinct coactivators, DRIP/mediator and SRC/p160, are differentially involved in vitamin D receptor transactivation during keratinocyte differentiation. Mol Endocrinol 17:2329–2339PubMedCrossRefGoogle Scholar
  88. Oda Y, Ishikawa MH, Hawker NP, Yun QC, Bikle DD (2007) Differential role of two VDR coactivators, DRIP205 and SRC-3, in keratinocyte proliferation and differentiation. J Steroid Biochem Mol Biol 103:776–780PubMedCrossRefGoogle Scholar
  89. Oda Y, Uchida Y, Moradian S, Crumrine D, Elias PM, Bikle DD (2008) Vitamin D receptor and coactivators SRC2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation. J Invest Dermatol 129:1367–1378PubMedCrossRefGoogle Scholar
  90. Palmer HG, Anjos-Afonso F, Carmeliet G, Takeda H, Watt FM (2008) The Vitamin D Receptor Is a Wnt Effector that Controls Hair Follicle Differentiation and Specifies Tumor Type in Adult Epidermis. PLoS ONE 3:e1483PubMedCrossRefGoogle Scholar
  91. Pillai S, Bikle D (1991) 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 146:94–100PubMedCrossRefGoogle Scholar
  92. Pillai S, Bikle D, Elias P (1988a) 1, 25-Dihydroxyvitamin D production and receptor binding in human keratinocytes varies with differentiation. J Biol Chem 263:5390–5395PubMedGoogle Scholar
  93. Pillai S, Bikle DD, Hincenbergs M, Elias PM (1988b) Biochemical and morphological ­characterization of growth and differentiation of normal human neonatal keratinocytes in a serum-free medium. J Cell Physiol 134:229–237PubMedCrossRefGoogle Scholar
  94. Pillai S, Bikle DD, Eessalu TE, Aggarwal BB, Elias PM (1989) Binding and biological effects of tumor necrosis factor alpha on cultured human neonatal foreskin keratinocytes. J Clin Invest 83:816–821PubMedCrossRefGoogle Scholar
  95. Pillai S, Bikle DD, Mancianti ML, Cline P, Hincenbergs M (1990) Calcium regulation of growth and differentiation of normal human keratinocytes: modulation of differentiation competence by stages of growth and extracellular calcium. J Cell Physiol 143:294–302PubMedCrossRefGoogle Scholar
  96. Pillai S, Bikle DD, Su MJ, Ratnam A, Abe J (1995) 1, 25-Dihydroxyvitamin D3 upregulates the phosphatidylinositol signaling pathway in human keratinocytes by increasing phospholipase C levels. J Clin Invest 96:602–609PubMedCrossRefGoogle Scholar
  97. Pinette KV, Yee YK, Amegadzie BY, Nagpal S (2003) Vitamin D receptor as a drug discovery target. Mini Rev Med Chem 3:193–204PubMedCrossRefGoogle Scholar
  98. Pokutta S, Weis WI (2007) Structure and mechanism of cadherins and catenins in cell-cell ­contacts. Annu Rev Cell Dev Biol 23:237–261PubMedCrossRefGoogle Scholar
  99. Punnonen K, Denning M, Lee E, Li L, Rhee SG, Yuspa SH (1993) Keratinocyte differentiation is associated with changes in the expression and regulation of phospholipase C isoenzymes. J Invest Dermatol 101:719–726PubMedCrossRefGoogle Scholar
  100. Rachez C, Lemon B, Suldan Z, Bromleigh V, Gamble M, Naar A, Erdjument-Bromage H, Tempst P, Freedman L (1999) Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 398:824–828PubMedCrossRefGoogle Scholar
  101. Rasmussen H, Wong M, Bikle D, Goodman DB (1972) Hormonal control of the renal conversion of 25-hydroxycholecalciferol to 1, 25-dihydroxycholecalciferol. J Clin Invest 51:2502–2504PubMedCrossRefGoogle Scholar
  102. Ratnam AV, Bikle DD, Su MJ, Pillai S (1996) Squamous carcinoma cell lines fail to respond to 1, 25-Dihydroxyvitamin D despite normal levels of the vitamin D receptor. J Invest Dermatol 106:522–525PubMedCrossRefGoogle Scholar
  103. Ratnam AV, Bikle DD, Cho JK (1999) 1, 25 dihydroxyvitamin D3 enhances the calcium response of keratinocytes. J Cell Physiol 178:188–196PubMedCrossRefGoogle Scholar
  104. Reeve L, Tanaka Y, DeLuca HF (1983) Studies on the site of 1, 25-dihydroxyvitamin D3 synthesis in vivo. J Biol Chem 258:3615–3617PubMedGoogle Scholar
  105. Rheinwald JG, Beckett MA (1980) Defective terminal differentiation in culture as a consistent and selectable character of malignant human keratinocytes. Cell 22:629–632PubMedCrossRefGoogle Scholar
  106. Rizk-Rabin M, Pavlovitch JH (1988) Effect of vitamin D deficiency and 1, 25-dihydroxycholecalciferol treatment on epidermal calcium-binding protein (ECaBP) RNA activity. Mol Cell Endocrinol 60:145–149PubMedCrossRefGoogle Scholar
  107. Robyr D, Wolffe A, Wahli W (2000) Nuclear hormone receptor coregulators in action: diversity for shared tasks. Mol Endocrinol 14:329–347PubMedCrossRefGoogle Scholar
  108. Rost CR, Bikle DD, Kaplan RA (1981) In vitro stimulation of 25-hydroxycholecalciferol 1 alpha-hydroxylation by parathyroid hormone in chick kidney slices: evidence for a role for adenosine 3′, 5′-monophosphate. Endocrinology 108:1002–1006PubMedCrossRefGoogle Scholar
  109. Rubin AL, Parenteau NL, Rice RH (1989) Coordination of keratinocyte programming in human SCC-13 squamous carcinoma and normal epidermal cells. J Cell Physiol 138:208–214PubMedCrossRefGoogle Scholar
  110. Ryynanen J, Jaakkola S, Engvall E, Peltonen J, Uitto J (1991) Expression of beta 4 integrins in human skin: comparison of epidermal distribution with beta 1-integrin epitopes, and modulation by calcium and vitamin D3 in cultured keratinocytes. J Invest Dermatol 97:562–567PubMedCrossRefGoogle Scholar
  111. Schauber J, Dorschner RA, Coda AB, Buchau AS, Liu PT, Kiken D, Helfrich YR, Kang S, Elalieh HZ, Steinmeyer A, Zugel U, Bikle DD, Modlin RL, Gallo RL (2007a) Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest 117:803–811PubMedCrossRefGoogle Scholar
  112. Schauber J, Oda Y, Buchau AS, Yun QC, Steinmeyer A, Zugel U, Bikle DD, Gallo RL (2007b) Histone Acetylation in Keratinocytes Enables Control of the Expression of Cathelicidin and CD14 by 1, 25-Dihydroxyvitamin D(3). J Invest Dermatol 128:816–824PubMedCrossRefGoogle Scholar
  113. Schurer NY, Elias PM (1991) The biochemistry and function of stratum corneum lipids. Adv Lipid Res 24:27–56PubMedGoogle Scholar
  114. Sebag M, Henderson J, Rhim J, Kremer R (1992) Relative resistance to 1, 25-dihydroxyvitamin D3 in a keratinocyte model of tumor progression. J Biol Chem 267:12162–12167PubMedGoogle Scholar
  115. Shultz TD, Fox J, Heath H 3rd, Kumar R (1983) Do tissues other than the kidney produce 1, 25-dihydroxyvitamin D3 in vivo? A reexamination. Proc Natl Acad Sci USA 80:1746–1750PubMedCrossRefGoogle Scholar
  116. Smith E, Walworth N, Holick M (1986) 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 86:709–714PubMedCrossRefGoogle Scholar
  117. Spanos E, Barrett DI, Chong KT, MacIntyre I (1978) Effect of oestrogen and 1, 25-dihydroxycholecalciferol on 25-hydroxycholecalciferol metabolism in primary chick kidney-cell cultures. Biochem J 174:231–236PubMedGoogle Scholar
  118. Steven AC, Bisher ME, Roop DR, Steinert PM (1990) Biosynthetic pathways of filaggrin and loricrin–two major proteins expressed by terminally differentiated epidermal keratinocytes. J Struct Biol 104:150–162PubMedCrossRefGoogle Scholar
  119. Stumpf W, Sar M, Reid F, Tanaka Y, DeLuca H (1979) Target cells for 1, 25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary and parathyroid. Science 206:1188–1190PubMedCrossRefGoogle Scholar
  120. Su MJ, Bikle DD, Mancianti ML, Pillai S (1994) 1, 25-Dihydroxyvitamin D3 potentiates the keratinocyte response to calcium. J Biol Chem 269:14723–14729PubMedGoogle Scholar
  121. Tang W, Ziboh VA (1991) Agonist/inositol trisphosphate-induced release of calcium from murine keratinocytes: a possible link with keratinocyte differentiation. J Invest Dermatol 96:134–138PubMedCrossRefGoogle Scholar
  122. Tang W, Ziboh VA, Isseroff RR, Martinez D (1987) Novel regulatory actions of 1 alpha, 25-­dihydroxyvitamin D3 on the metabolism of polyphosphoinositides in murine epidermal keratinocytes. J Cell Physiol 132:131–136PubMedCrossRefGoogle Scholar
  123. Tang W, Ziboh VA, Isseroff R, Martinez D (1988) Turnover of inositol phospholipids in cultured murine keratinocytes: possible involvement of inositol triphosphate in cellular differentiation. J Invest Dermatol 90:37–43PubMedCrossRefGoogle Scholar
  124. Tracher S, Rice R (1985) Keratinocyte-specific transglutaminase of cultured human epidermal cells: relation to cross-linked envelope formation and terminal differentiation. Cell 40:685–695CrossRefGoogle Scholar
  125. Trechsel U, Bonjour JP, Fleisch H (1979) Regulation of the metabolism of 25-hydroxyvitamin D3 in primary cultures of chick kidney cells. J Clin Invest 64:206–217PubMedCrossRefGoogle Scholar
  126. Trefzer U, Brockhaus M, Lotscher H, Parlow F, Budnik A, Grewe M, Christoph H, Kapp A, Schopf E, Luger TA et al. (1993) The 55-kD tumor necrosis factor receptor on human keratinocytes is regulated by tumor necrosis factor-alpha and by ultraviolet B radiation. J Clin Invest 92:462–470PubMedCrossRefGoogle Scholar
  127. Tu CL, Chang W, Bikle DD (2005) Phospholipase cgamma1 is required for activation of store-operated channels in human keratinocytes. J Invest Dermatol 124:187–197PubMedCrossRefGoogle Scholar
  128. Tu CL, Chang W, Bikle DD (2007) The role of the calcium sensing receptor in regulating intracellular calcium handling in human epidermal keratinocytes. J Invest Dermatol 127:1074–1083PubMedCrossRefGoogle Scholar
  129. Tu CL, Chang W, Xie Z, Bikle DD (2008) Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human ­epidermal keratinocytes. J Biol Chem 283:3519–3528PubMedCrossRefGoogle Scholar
  130. van Dam RM, Huang Z, Giovannucci E, Rimm EB, Hunter DJ, Colditz GA, Stampfer MJ, Willett WC (2000) Diet and basal cell carcinoma of the skin in a prospective cohort of men. Am J Clin Nutr 71:135–141PubMedGoogle Scholar
  131. Verlinden L, Verstuyf A, Convents R, Marcelis S, Van Camp M, Bouillon R (1998) Action of 1, 25(OH)2D3 on the cell cycle genes, cyclin D1, p21 and p27 in MCF-7 cells. Mol Cell Endocrinol 142:57–65PubMedCrossRefGoogle Scholar
  132. Voegel JJ, Heine MJ, Zechel C, Chambon P, Gronemeyer H (1996) TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J 15:3667–3675PubMedGoogle Scholar
  133. Warhol MJ, Roth J, Lucocq JM, Pinkus GS, Rice RH (1985) Immuno-ultrastructural localization of involucrin in squamous epithelium and cultured keratinocytes. J Histochem Cytochem 33:141–149PubMedGoogle Scholar
  134. Weinstock MA, Stampfer MJ, Lew RA, Willett WC, Sober AJ (1992) Case-control study of ­melanoma and dietary vitamin D: implications for advocacy of sun protection and sunscreen use. J Invest Dermatol 98:809–811PubMedCrossRefGoogle Scholar
  135. Wood LC, Elias PM, Sequeira-Martin SM, Grunfeld C, Feingold KR (1994) Occlusion lowers cytokine mRNA levels in essential fatty acid-deficient and normal mouse epidermis, but not after acute barrier disruption. J Invest Dermatol 103:834–838PubMedCrossRefGoogle Scholar
  136. Xie Z, Bikle DD (1999) Phospholipase C-gamma1 is required for calcium-induced keratinocyte differentiation. J Biol Chem 274:20421–20424PubMedCrossRefGoogle Scholar
  137. Xie Z, Bikle DD (2007) 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 282:8695–8703PubMedCrossRefGoogle Scholar
  138. Xie Z, Komuves L, Yu QC, Elalieh H, Ng DC, Leary C, Chang S, Crumrine D, Yoshizawa T, Kato S, Bikle DD (2002a) Lack of the vitamin D receptor is associated with reduced epidermal differentiation and hair follicle growth. J Invest Dermatol 118:11–16PubMedCrossRefGoogle Scholar
  139. Xie Z, Munson SJ, Huang N, Portale AA, Miller WL, Bikle DD (2002b) The mechanism of 1, 25-dihydroxyvitamin D(3) autoregulation in keratinocytes. J Biol Chem 277:36987–36990PubMedCrossRefGoogle Scholar
  140. Xie Z, Singleton PA, Bourguignon LY, Bikle DD (2005) Calcium-induced human keratinocyte differentiation requires src- and fyn-mediated phosphatidylinositol 3-kinase-dependent activation of phospholipase C-gamma1. Mol Biol Cell 16:3236–3246PubMedCrossRefGoogle Scholar
  141. Xie Z, Chang S, Oda Y, Bikle DD (2006) Hairless suppresses vitamin D receptor transactivation in human keratinocytes. Endocrinology 147:314–323PubMedCrossRefGoogle Scholar
  142. Xie Z, Chang SM, Pennypacker SD, Liao EY, Bikle DD (2009) Phosphatidylinositol-4-phosphate 5-kinase 1alpha mediates extracellular calcium-induced keratinocyte differentiation. Mol Biol Cell 20:1695–1704PubMedCrossRefGoogle Scholar
  143. Yada Y, Ozeki T, Meguro S, Mori S, Nozawa Y (1989) Signal transduction in the onset of terminal keratinocyte differentiation induced by 1 alpha, 25-dihydroxyvitamin D3: role of protein kinase C translocation. Biochem Biophys Res Commun 163:1517–1522PubMedCrossRefGoogle Scholar
  144. Yoneda K, Fujimoto T, Imamura S, Ogawa K (1990) Distribution of fodrin in the keratinocyte in vivo and in vitro. J Invest Dermatol 94:724–729PubMedCrossRefGoogle Scholar
  145. Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, Kawakami T, Arioka K, Sato H, Uchiyama Y, Masushige S, Fukamizu A, Matsumoto T, Kato S (1997) Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 16:391–396PubMedCrossRefGoogle Scholar
  146. Young MR, Lathers DM (2005) Combination docetaxel plus vitamin D(3) as an immune therapy in animals bearing squamous cell carcinomas. Otolaryngol Head Neck Surg 133:611–618PubMedCrossRefGoogle Scholar
  147. Yuan C, Ito M, Fondell J, Fu Z, Roeder R (1998) The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. Proc Natl Acad Sci USA 95:7939–7944PubMedCrossRefGoogle Scholar
  148. Yuspa SH, Kilkenny AE, Steinert PM, Roop DR (1989) Expression of murine epidermal differentiation markers is tightly regulated by restricted extracellular calcium concentrations in vitro. J Cell Biol 109:1207–1217PubMedCrossRefGoogle Scholar
  149. Zamansky GB, Nguyen U, Chou IN (1991) An immunofluorescence study of the calcium-induced coordinated reorganization of microfilaments, keratin intermediate filaments, and microtubules in cultured human epidermal keratinocytes. J Invest Dermatol 97:985–994PubMedCrossRefGoogle Scholar
  150. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, Hewison M (2001) Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 86:888–894PubMedCrossRefGoogle Scholar
  151. Zhu Y, Qi C, Calandra C, Rao MS, Reddy JK (1996) Cloning and identification of mouse steroid receptor coactivator-1 (mSRC-1). as a coactivator of peroxisome proliferator-activated receptor gamma. Gene Expr 6:185–195PubMedGoogle Scholar
  152. Zinser GM, Sundberg JP, Welsh J (2002) Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis. Carcinogenesis 23:2103–2109PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Endocrine UnitUniversity of CaliforniaSan FranciscoUSA

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