Skip to main content
SpringerLink
Log in

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

  • Chapter
  • First Online:
Signaling Pathways in Squamous Cancer

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Belandia B, Parker MG (2003) Nuclear receptors: a rendezvous for chromatin remodeling factors. Cell 114:277–280

    Article  PubMed  CAS  Google Scholar 

  • Berridge MJ (1993) Inositol trisphosphate and calcium signalling. Nature 361:315–325

    Article  PubMed  CAS  Google Scholar 

  • Bikle D, Nemanic M, Whitney J, Elias P (1986a) Neonatal human foreskin keratinocytes produce 1, 25-dihydroxyvitamin D3. Biochemistry 25:1545–1548

    Article  PubMed  CAS  Google Scholar 

  • Bikle DD, Nemanic MK, Gee E, Elias P (1986b) 1, 25-Dihydroxyvitamin D3 production by human keratinocytes. Kinetics and regulation. J Clin Invest 78:557–566

    Article  PubMed  CAS  Google Scholar 

  • Bikle DD, Pillai S, Gee E, Hincenbergs M (1989) Regulation of 1, 25-dihydroxyvitamin D production in human keratinocytes by interferon-gamma. Endocrinology 124:655–660

    Article  PubMed  CAS  Google Scholar 

  • 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 97:435–441

    Article  PubMed  CAS  Google Scholar 

  • Bikle DD, Pillai S, Gee E, Hincenbergs M (1991b) Tumor necrosis factor-alpha regulation of 1, 25-dihydroxyvitamin D production by human keratinocytes. Endocrinology 129:33–38

    Article  PubMed  CAS  Google Scholar 

  • Bikle DD, Halloran BP, Riviere JE (1994) Production of 1, 25 dihydroxyvitamin D3 by perfused pig skin. J Invest Dermatol 102:796–798

    Article  PubMed  CAS  Google Scholar 

  • 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 97:1085–1093

    Article  PubMed  CAS  Google Scholar 

  • 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 119:1109–1113

    Article  PubMed  CAS  Google Scholar 

  • Bikle DD, Tu CL, Xie Z, Oda Y (2003) Vitamin D regulated keratinocyte differentiation: role of coactivators. J Cell Biochem 88:290–295

    Article  PubMed  CAS  Google Scholar 

  • 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 122:984–992

    Article  PubMed  CAS  Google Scholar 

  • Bittiner B, Bleehen SS, MacNeil S (1991) 1 alpha, 25(OH)2 vitamin D3 increases intracellular calcium in human keratinocytes. Br J Dermatol 124:230–235

    Article  PubMed  CAS  Google Scholar 

  • Bollag WB, Ducote J, Harmon CS (1995) Biphasic effect of 1, 25-dihydroxyvitamin D3 on ­primary mouse epidermal keratinocyte proliferation. J Cell Physiol 163:248–256

    Article  PubMed  CAS  Google Scholar 

  • 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 137:1302–1317

    PubMed  CAS  Google Scholar 

  • 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 366:575–580

    Article  PubMed  CAS  Google Scholar 

  • Calautti E, Missero C, Stein PL, Ezzell RM, Dotto GP (1995) fyn tyrosine kinase is involved in keratinocyte differentiation control. Genes Dev 9:2279–2291

    Article  PubMed  CAS  Google Scholar 

  • 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 141:1449–1465

    Article  PubMed  CAS  Google Scholar 

  • Carlberg C, Polly P (1998) Gene regulation by vitamin D3. Crit Rev Eukaryot Gene Expr 8:19–42

    PubMed  CAS  Google Scholar 

  • Carpenter G, Ji Q (1999) Phospholipase C-gamma as a signal-transducing element. Exp Cell Res 253:15–24

    Article  PubMed  CAS  Google Scholar 

  • Chen JD, Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377:454–457

    Article  PubMed  CAS  Google Scholar 

  • 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 7:1671–1679

    Article  PubMed  CAS  Google Scholar 

  • 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 108:1083–1086

    Article  PubMed  CAS  Google Scholar 

  • Dale BA, Resing KA, Lonsdale-Eccles JD (1985) Filaggrin: a keratin filament associated protein. Ann NY Acad Sci 455:330–342

    Article  PubMed  CAS  Google Scholar 

  • 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 102:1767–1777

    Article  PubMed  CAS  Google Scholar 

  • Eisman JA, Martin TJ, MacIntyre I, Moseley JM (1979) 1, 25-dihydroxyvitamin-D-receptor in breast cancer cells. Lancet 2:1335–1336

    Article  PubMed  CAS  Google Scholar 

  • 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 91:3–10

    Article  PubMed  CAS  Google Scholar 

  • 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 119:1128–1136

    Article  PubMed  CAS  Google Scholar 

  • 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 282:10953–10962

    Article  PubMed  CAS  Google Scholar 

  • 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 128:2508–2571

    Article  PubMed  CAS  Google Scholar 

  • 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 280:1747–1749

    Article  PubMed  CAS  Google Scholar 

  • 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 11:1961–1970

    Article  PubMed  CAS  Google Scholar 

  • 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 1:307–309

    Article  PubMed  CAS  Google Scholar 

  • 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 19:614–622

    Article  PubMed  CAS  Google Scholar 

  • 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 270:12919–12925

    Article  PubMed  CAS  Google Scholar 

  • Gniadecki R (1996) Stimulation versus inhibition of keratinocyte growth by 1, 25-Dihydroxyvitamin D3: dependence on cell culture conditions. J Invest Dermatol 106:510–516

    Article  PubMed  CAS  Google Scholar 

  • Guo M, Kim L, Akiyama S, Gralnick H, Yamada K, Grinnell F (1991) Altered processing of integrin receptors during keratinocyte activation. Exp Cell Res 195:315–322

    Article  PubMed  CAS  Google Scholar 

  • Hanchette CL, Schwartz GG (1992) Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation. Cancer 70:2861–2869

    Article  PubMed  CAS  Google Scholar 

  • 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 18:252–257

    PubMed  CAS  Google Scholar 

  • 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 127:874–880

    Article  PubMed  CAS  Google Scholar 

  • 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 387:43–48

    Article  PubMed  CAS  Google Scholar 

  • Hennings H, Holbrook KA (1983) Calcium regulation of cell-cell contact and differentiation of epidermal cells in culture. An ultrastructural study. Exp Cell Res 143:127–142

    Article  PubMed  CAS  Google Scholar 

  • 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 19:245–54

    Article  PubMed  CAS  Google Scholar 

  • Hohl D (1990) Cornified cell envelope. Dermatologica 180:201–211

    Article  PubMed  CAS  Google Scholar 

  • 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 96:414–418

    Article  PubMed  CAS  Google Scholar 

  • Holick MF (2004) Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 79:362–371

    PubMed  CAS  Google Scholar 

  • Holleran WM, Takagi Y, Uchida Y (2006) Epidermal sphingolipids: metabolism, function, and roles in skin disorders. FEBS Lett 580:5456–5466

    Article  PubMed  CAS  Google Scholar 

  • 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 93:4948–4952

    Article  PubMed  CAS  Google Scholar 

  • 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 84:461–464

    Article  PubMed  CAS  Google Scholar 

  • 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 113:1950–1957

    Article  PubMed  CAS  Google Scholar 

  • 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 278:38665–38674

    Article  PubMed  CAS  Google Scholar 

  • 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 268:377–384

    PubMed  CAS  Google Scholar 

  • 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 2:231–239

    Article  PubMed  CAS  Google Scholar 

  • 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 127:1250–1260

    Article  PubMed  CAS  Google Scholar 

  • 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 135:1793–1798

    Article  PubMed  CAS  Google Scholar 

  • Jaken S, Yuspa SH (1988) Early signals for keratinocyte differentiation: role of Ca2 + -mediated inositol lipid metabolism in normal and neoplastic epidermal cells. Carcinogenesis 9:1033–1038

    Article  PubMed  CAS  Google Scholar 

  • 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 164:259–269

    PubMed  CAS  Google Scholar 

  • 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 143:907–917

    PubMed  CAS  Google Scholar 

  • 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 151:579–587

    Article  PubMed  CAS  Google Scholar 

  • Kira M, Kobayashi T, Yoshikawa K (2003) Vitamin D and the skin. J Dermatol 30:429–37

    PubMed  CAS  Google Scholar 

  • 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 8:153–163

    Article  PubMed  CAS  Google Scholar 

  • 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 87:884–893

    Article  PubMed  CAS  Google Scholar 

  • 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 377:451–454

    Article  PubMed  CAS  Google Scholar 

  • 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 53:422–430

    Article  PubMed  CAS  Google Scholar 

  • Lee E, Yuspa SH (1991) Aluminum fluoride stimulates inositol phosphate metabolism and inhibits expression of differentiation markers in mouse keratinocytes. J Cell Physiol 148:106–115

    Article  PubMed  CAS  Google Scholar 

  • 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 291:507–510

    Article  PubMed  CAS  Google Scholar 

  • 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 117:1179–1185

    Article  PubMed  CAS  Google Scholar 

  • 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 94:9831–9835

    Article  PubMed  CAS  Google Scholar 

  • MacLaughlin JA, Cantley LC, Holick MF (1990) 1, 25(OH)2D3 increases calcium and phosphatidylinositol metabolism in differentiating cultured human keratinocytes. J Nutr Biochem 1:81–87

    Article  PubMed  CAS  Google Scholar 

  • 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 112:761–773

    Article  PubMed  CAS  Google Scholar 

  • Masumoto O, Ohyama Y, Okuda K (1988) Purification and characterization of vitamin D 25-hydroxylase from rat liver mitochondria. J Biol Chem 263:14256–14260

    PubMed  CAS  Google Scholar 

  • 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 166:916–923

    Article  PubMed  CAS  Google Scholar 

  • 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 1092:311–318

    Article  PubMed  CAS  Google Scholar 

  • 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 111:1198–1201

    Article  PubMed  CAS  Google Scholar 

  • 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 26:379–387

    Article  PubMed  CAS  Google Scholar 

  • 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 61:1103–1112

    Article  PubMed  CAS  Google Scholar 

  • Menon GK, Grayson S, Elias PM (1985) Ionic calcium reservoirs in mammalian epidermis: ultrastructural localization by ion-capture cytochemistry. J Invest Dermatol 84:508–512

    Article  PubMed  CAS  Google Scholar 

  • 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 37:257–267

    Article  PubMed  CAS  Google Scholar 

  • 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 97:230–29

    Article  PubMed  CAS  Google Scholar 

  • 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 31:11–24

    Article  PubMed  CAS  Google Scholar 

  • Moras D, Gronemeyer H (1998) The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 10:384–391

    Article  PubMed  CAS  Google Scholar 

  • 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 548:321–330

    Article  PubMed  CAS  Google Scholar 

  • 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 264:11228–11235

    PubMed  CAS  Google Scholar 

  • 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 89:373–380

    Article  PubMed  CAS  Google Scholar 

  • Ng DC, Su MJ, Kim R, Bikle DD (1996) Regulation of involucrin gene expression by calcium in normal human keratinocytes. Front Biosci 1:a16–24

    PubMed  CAS  Google Scholar 

  • 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 275:1183–1190

    Article  PubMed  CAS  Google Scholar 

  • 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 17:2329–2339

    Article  PubMed  CAS  Google Scholar 

  • 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 103:776–780

    Article  PubMed  CAS  Google Scholar 

  • 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 129:1367–1378

    Article  PubMed  CAS  Google Scholar 

  • 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:e1483

    Article  PubMed  CAS  Google Scholar 

  • 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 146:94–100

    Article  PubMed  CAS  Google Scholar 

  • Pillai S, Bikle D, Elias P (1988a) 1, 25-Dihydroxyvitamin D production and receptor binding in human keratinocytes varies with differentiation. J Biol Chem 263:5390–5395

    PubMed  CAS  Google Scholar 

  • 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 134:229–237

    Article  PubMed  CAS  Google Scholar 

  • 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 83:816–821

    Article  PubMed  CAS  Google Scholar 

  • 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 143:294–302

    Article  PubMed  CAS  Google Scholar 

  • 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 96:602–609

    Article  PubMed  CAS  Google Scholar 

  • Pinette KV, Yee YK, Amegadzie BY, Nagpal S (2003) Vitamin D receptor as a drug discovery target. Mini Rev Med Chem 3:193–204

    Article  PubMed  CAS  Google Scholar 

  • Pokutta S, Weis WI (2007) Structure and mechanism of cadherins and catenins in cell-cell ­contacts. Annu Rev Cell Dev Biol 23:237–261

    Article  PubMed  CAS  Google Scholar 

  • 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 101:719–726

    Article  PubMed  CAS  Google Scholar 

  • 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 398:824–828

    Article  PubMed  CAS  Google Scholar 

  • 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 51:2502–2504

    Article  PubMed  CAS  Google Scholar 

  • 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 106:522–525

    Article  PubMed  CAS  Google Scholar 

  • Ratnam AV, Bikle DD, Cho JK (1999) 1, 25 dihydroxyvitamin D3 enhances the calcium response of keratinocytes. J Cell Physiol 178:188–196

    Article  PubMed  CAS  Google Scholar 

  • Reeve L, Tanaka Y, DeLuca HF (1983) Studies on the site of 1, 25-dihydroxyvitamin D3 synthesis in vivo. J Biol Chem 258:3615–3617

    PubMed  CAS  Google Scholar 

  • Rheinwald JG, Beckett MA (1980) Defective terminal differentiation in culture as a consistent and selectable character of malignant human keratinocytes. Cell 22:629–632

    Article  PubMed  CAS  Google Scholar 

  • 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 60:145–149

    Article  PubMed  CAS  Google Scholar 

  • Robyr D, Wolffe A, Wahli W (2000) Nuclear hormone receptor coregulators in action: diversity for shared tasks. Mol Endocrinol 14:329–347

    Article  PubMed  CAS  Google Scholar 

  • 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 108:1002–1006

    Article  PubMed  CAS  Google Scholar 

  • Rubin AL, Parenteau NL, Rice RH (1989) Coordination of keratinocyte programming in human SCC-13 squamous carcinoma and normal epidermal cells. J Cell Physiol 138:208–214

    Article  PubMed  CAS  Google Scholar 

  • 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 97:562–567

    Article  PubMed  CAS  Google Scholar 

  • 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 117:803–811

    Article  PubMed  CAS  Google Scholar 

  • 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 128:816–824

    Article  PubMed  CAS  Google Scholar 

  • Schurer NY, Elias PM (1991) The biochemistry and function of stratum corneum lipids. Adv Lipid Res 24:27–56

    PubMed  CAS  Google Scholar 

  • 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 267:12162–12167

    PubMed  CAS  Google Scholar 

  • 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 80:1746–1750

    Article  PubMed  CAS  Google Scholar 

  • 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 86:709–714

    Article  PubMed  CAS  Google Scholar 

  • 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 174:231–236

    PubMed  CAS  Google Scholar 

  • 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 104:150–162

    Article  PubMed  CAS  Google Scholar 

  • 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 206:1188–1190

    Article  PubMed  CAS  Google Scholar 

  • Su MJ, Bikle DD, Mancianti ML, Pillai S (1994) 1, 25-Dihydroxyvitamin D3 potentiates the keratinocyte response to calcium. J Biol Chem 269:14723–14729

    PubMed  CAS  Google Scholar 

  • Tang W, Ziboh VA (1991) Agonist/inositol trisphosphate-induced release of calcium from murine keratinocytes: a possible link with keratinocyte differentiation. J Invest Dermatol 96:134–138

    Article  PubMed  CAS  Google Scholar 

  • 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 132:131–136

    Article  PubMed  CAS  Google Scholar 

  • 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 90:37–43

    Article  PubMed  CAS  Google Scholar 

  • Tracher S, Rice R (1985) Keratinocyte-specific transglutaminase of cultured human epidermal cells: relation to cross-linked envelope formation and terminal differentiation. Cell 40:685–695

    Article  Google Scholar 

  • 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 64:206–217

    Article  PubMed  CAS  Google Scholar 

  • 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 92:462–470

    Article  PubMed  CAS  Google Scholar 

  • Tu CL, Chang W, Bikle DD (2005) Phospholipase cgamma1 is required for activation of store-operated channels in human keratinocytes. J Invest Dermatol 124:187–197

    Article  PubMed  CAS  Google Scholar 

  • 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 127:1074–1083

    Article  PubMed  CAS  Google Scholar 

  • 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 283:3519–3528

    Article  PubMed  CAS  Google Scholar 

  • 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 71:135–141

    PubMed  Google Scholar 

  • 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 142:57–65

    Article  PubMed  CAS  Google Scholar 

  • 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 15:3667–3675

    PubMed  CAS  Google Scholar 

  • 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 33:141–149

    PubMed  CAS  Google Scholar 

  • 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 98:809–811

    Article  PubMed  CAS  Google Scholar 

  • 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 103:834–838

    Article  PubMed  CAS  Google Scholar 

  • Xie Z, Bikle DD (1999) Phospholipase C-gamma1 is required for calcium-induced keratinocyte differentiation. J Biol Chem 274:20421–20424

    Article  PubMed  CAS  Google Scholar 

  • 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 282:8695–8703

    Article  PubMed  CAS  Google Scholar 

  • 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 118:11–16

    Article  PubMed  CAS  Google Scholar 

  • 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 277:36987–36990

    Article  PubMed  CAS  Google Scholar 

  • 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 16:3236–3246

    Article  PubMed  CAS  Google Scholar 

  • Xie Z, Chang S, Oda Y, Bikle DD (2006) Hairless suppresses vitamin D receptor transactivation in human keratinocytes. Endocrinology 147:314–323

    Article  PubMed  CAS  Google Scholar 

  • 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 20:1695–1704

    Article  PubMed  CAS  Google Scholar 

  • 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 163:1517–1522

    Article  PubMed  CAS  Google Scholar 

  • Yoneda K, Fujimoto T, Imamura S, Ogawa K (1990) Distribution of fodrin in the keratinocyte in vivo and in vitro. J Invest Dermatol 94:724–729

    Article  PubMed  CAS  Google Scholar 

  • 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 16:391–396

    Article  PubMed  CAS  Google Scholar 

  • 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 133:611–618

    Article  PubMed  Google Scholar 

  • 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 95:7939–7944

    Article  PubMed  CAS  Google Scholar 

  • 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 109:1207–1217

    Article  PubMed  CAS  Google Scholar 

  • 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 97:985–994

    Article  PubMed  CAS  Google Scholar 

  • 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 86:888–894

    Article  PubMed  CAS  Google Scholar 

  • 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 6:185–195

    PubMed  CAS  Google Scholar 

  • Zinser GM, Sundberg JP, Welsh J (2002) Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis. Carcinogenesis 23:2103–2109

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Endocrine Unit, University of California, San Francisco, CA, USA

    Arnaud Teichert

Authors
  1. Arnaud Teichert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel D. Bikle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arnaud Teichert .

Editor information

Editors and Affiliations

  1. Center for Molecular Toxicology &, Carcinogenesis, Pennsylvania State University, University Park, 16801, Pennsylvania, USA

    Adam B. Glick

  2. National Institute on Deafness &, Other Communication Disorders, National Institute of Health, Bethesda, 20892, Maryland, USA

    Carter Van Waes

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Teichert, A., Bikle, D.D. (2011). Regulation of Keratinocyte Differentiation by Vitamin D and Its Relationship to Squamous Cell Carcinoma. In: Glick, A., Waes, C. (eds) Signaling Pathways in Squamous Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7203-3_14

Download citation

Publish with us

Policies and ethics

Search

Navigation