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The Molecular Cancer Biology of the VDR

  • James Thorne
  • Moray J. Campbell
Chapter

Abstract

The development of an understanding of the role the vitamin D receptor (VDR) endocrine system plays to regulate serum calcium levels began approximately three centuries ago with the first formal descriptions of rickets. The parallel appreciation of a role for the VDR in cancer biology began approximately 3 decades ago and subsequently a remarkable increase has occurred in the understanding of its actions in normal and malignant systems.

Principally, much of this understanding has focused on understanding the extent and mechanism by which the VDR influences expression of multiple proteins whose combined actions are to govern cell cycle progression, induce differentiation, and contribute to the regulation of programmed cell death, perhaps in response to loss of genomic integrity. Predominantly, although not exclusively, these increases in target proteins reflect the transcriptional control exerted via the VDR. Reflecting the expanding understanding of how chromatin architecture is sensed and altered by transcription factors, the actions of the VDR have been defined through the large transcriptional complexes it is found in. The diversity of these complexes is large, and presumably underpins the pleiotropic biological actions that the VDR is associated with. The VDR is neither mutated nor deleted in malignancy but instead polymorphic variation distorts its ability to function, as indeed does expression of a number of associated cofactors, thereby skewing the ability to transactivate target genes.

Exploitation of this understanding into cancer therapeutic settings may occur through several routes, but perhaps a more systems orientated approach may yield insight by identifying and modeling points where the VDR, and closely related nuclear receptors, exert the most dominant control over cellular processes such as cell cycle control.

Keywords

HDAC Inhibitor Lithocholic Acid Downstream Regulatory Element Antagonist Modulator ApaI Polymorphism Transcriptional Responsiveness 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

AR

Androgen receptor

bHLH

Bacis helix loop helix

9 cRA

9 cis retinoic acid

1α,25(OH)2D3

1α,25DihydroxyvitaminD3

DREAM

Downstream regulatory element antagonist modulator

ER

Estrogen receptor

FXR

Farnesoid X-activated receptor

HDAC

Histone deacetylase

HDACi

Histone deacetylase inhibitor

HSP

Heat shock protein

LCOR

Ligand-dependent nuclear receptor corepressor

LCA

Lithocholic acid

LXR

Liver X receptor

NCOR1

Nuclear receptor corepressor 1

NCOR2/SMRT

Silencing mediator of retinoid and thyroid hormone ­receptors/Nuclear receptor corepressor 2

NR

Nuclear receptor

PPAR

Peroxisome proliferator activated receptor

RAR

Retinoic acid receptor

RXR

Retinoid X receptor

SLIRP

SRA stem loop-interacting RNA-binding protein

SRC

Steroid receptor coactivator

TRIP2/DRIP205

Thyroid hormone receptor interactor 2

TRIP15/COPS2/Alien

Thyroid hormone receptor interactor 15

VDR

Vitamin D receptor

References

  1. 1.
    Deeb KK, Trump DL, Johnson CS (2007) Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 7:684–700PubMedGoogle Scholar
  2. 2.
    Imawari M, Kida K, Goodman DS (1976) The transport of vitamin D and its 25-hydroxy metabolite in human plasma. Isolation and partial characterization of vitamin D and 25-hydroxyvitamin D binding protein. J Clin Invest 58:514–523PubMedGoogle Scholar
  3. 3.
    Bouillon R, Van Assche FA, Van Baelen H, Heyns W, De Moor P (1981) Influence of the vitamin D-binding protein on the serum concentration of 1, 25-dihydroxyvitamin D3. Significance of the free 1, 25-dihydroxyvitamin D3 concentration. J Clin Invest 67:589–596PubMedGoogle Scholar
  4. 4.
    Nykjaer A et al (1999) An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 96:507–515PubMedGoogle Scholar
  5. 5.
    Barsony J, Renyi I, McKoy W (1997) Subcellular distribution of normal and mutant vitamin D receptors in living cells. Studies with a novel fluorescent ligand. J Biol Chem 272:5774–5782PubMedGoogle Scholar
  6. 6.
    Huhtakangas JA, Olivera CJ, Bishop JE, Zanello LP, Norman AW (2004) The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha, 25(OH)2-vitamin D3 in vivo and in vitro. Mol Endocrinol 18:2660–2671PubMedGoogle Scholar
  7. 7.
    Boyan BD et al (2006) Regulation of growth plate chondrocytes by 1, 25-dihydroxyvitamin D3 requires caveolae and caveolin-1. J Bone Miner Res 21:1637–1647PubMedGoogle Scholar
  8. 8.
    Prufer K, Racz A, Lin GC, Barsony J (2000) Dimerization with retinoid X receptors promotes nuclear localization and subnuclear targeting of vitamin D receptors. J Biol Chem 275:41114–41123PubMedGoogle Scholar
  9. 9.
    Yasmin R, Williams RM, Xu M, Noy N (2005) Nuclear import of the retinoid X receptor, the vitamin D receptor, and their mutual heterodimer. J Biol Chem 280:40152–40160PubMedGoogle Scholar
  10. 10.
    Quack M, Carlberg C (2000) The impact of functional vitamin D(3) receptor conformations on DNA-dependent vitamin D(3) signaling. Mol Pharmacol 57:375–384PubMedGoogle Scholar
  11. 11.
    Renaud JP et al (1995) Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature 378:681–689PubMedGoogle Scholar
  12. 12.
    Nakabayashi M et al (2008) Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs: structural basis for vitamin D receptor antagonism and partial agonism. J Med Chem 51:5320–5329PubMedGoogle Scholar
  13. 13.
    Carlberg C, Molnar F (2006) Detailed molecular understanding of agonistic and antagonistic vitamin D receptor ligands. Curr Top Med Chem 6:1243–1253PubMedGoogle Scholar
  14. 14.
    Saramaki A et al (2009) Cyclical chromatin looping and transcription factor association on the regulatory regions of the p21 (CDKN1A) gene in response to 1alpha, 25-dihydroxyvitamin D3. J Biol Chem 284(12):8073–82PubMedGoogle Scholar
  15. 15.
    Kim JY, Son YL, Lee YC (2009) Involvement of SMRT corepressor in transcriptional repression by the vitamin D receptor. Mol Endocrinol 23:251–264PubMedGoogle Scholar
  16. 16.
    Li J et al (2000) Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J 19:4342–4350PubMedGoogle Scholar
  17. 17.
    Malinen M et al (2007) Distinct HDACs regulate the transcriptional response of human cyclin-dependent kinase inhibitor genes to trichostatin A and 1{alpha}, 25-dihydroxyvitamin D3. Nucleic Acids Res 36(1):121–32PubMedGoogle Scholar
  18. 18.
    Yoon HG et al (2003) Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1. EMBO J 22:1336–1346PubMedGoogle Scholar
  19. 19.
    Alenghat T, Yu J, Lazar MA (2006) The N-CoR complex enables chromatin remodeler SNF2H to enhance repression by thyroid hormone receptor. EMBO J 25(17):3966–74PubMedGoogle Scholar
  20. 20.
    Yu C et al (2005) The nuclear receptor corepressors NCoR and SMRT decrease PPARgamma transcriptional activity and repress 3T3-L1 adipogenesis. J Biol Chem 280(14):13600–5PubMedGoogle Scholar
  21. 21.
    Oda Y et al (2003) Two distinct coactivators, DRIP/mediator and SRC/p160, are differentially involved in vitamin D receptor transactivation during keratinocyte differentiation. Mol Endocrinol 17:2329–2339PubMedGoogle Scholar
  22. 22.
    Rachez C et al (2000) The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes. Mol Cell Biol 20:2718–2726PubMedGoogle Scholar
  23. 23.
    Saramaki A, Banwell CM, Campbell MJ, Carlberg C (2006) Regulation of the human p21(waf1/cip1) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor. Nucleic Acids Res 34:543–554PubMedGoogle Scholar
  24. 24.
    Vaisanen S, Dunlop TW, Sinkkonen L, Frank C, Carlberg C (2005) Spatio-temporal Activation of Chromatin on the Human CYP24 Gene Promoter in the Presence of 1alpha, 25-Dihydroxyvitamin D(3). J Mol Biol 350(1):65–77PubMedGoogle Scholar
  25. 25.
    Zella LA, Kim S, Shevde NK, Pike JW (2006) Enhancers located within two introns of the vitamin D receptor gene mediate transscriptional autoregulation by 1, 25-dihydroxyvitamin D3. Mol Endocrinol 103(3–5):435–9Google Scholar
  26. 26.
    Kim S, Shevde NK, Pike JW (2005) 1, 25-Dihydroxyvitamin D3 stimulates cyclic vitamin D receptor/retinoid X receptor DNA-binding, co-activator recruitment, and histone acetylation in intact osteoblasts. J Bone Miner Res 20:305–317PubMedGoogle Scholar
  27. 27.
    Seo YK et al (2007) Xenobiotic- and vitamin D-responsive induction of the steroid/bile acid-sulfotransferase Sult2A1 in young and old mice: the role of a gene enhancer in the liver chromatin. Gene 386:218–223PubMedGoogle Scholar
  28. 28.
    Meyer MB, Watanuki M, Kim S, Shevde NK, Pike JW (2006) The human TRPV6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1, 25-dihydroxyvitamin D3 in intestinal cells. Mol Endocrinol 20(6):1447–61PubMedGoogle Scholar
  29. 29.
    Reid G et al (2003) Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. Mol Cell 11:695–707PubMedGoogle Scholar
  30. 30.
    Metivier R et al (2003) Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115:751–763PubMedGoogle Scholar
  31. 31.
    Yang X et al (2006) Nuclear receptor expression links the circadian clock to metabolism. Cell 126:801–810PubMedGoogle Scholar
  32. 32.
    Carroll JS et al (2006) Genome-wide analysis of estrogen receptor binding sites. Nat Genet 38:1289–1297PubMedGoogle Scholar
  33. 33.
    Efer R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3:859–868Google Scholar
  34. 34.
    Watt FM, Frye M, Benitah SA (2008) MYC in mammalian epidermis: how can an oncogene stimulate differentiation? Nat Rev Cancer 8:234–242PubMedGoogle Scholar
  35. 35.
    Thorne JL, Campbell MJ, Turner BM (2009) Transcription factors, chromatin and cancer. Int J Biochem Cell Biol 41:164–175PubMedGoogle Scholar
  36. 36.
    Lefterova MI et al (2008) PPAR{gamma} and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev 22:2941–2952PubMedGoogle Scholar
  37. 37.
    Lupien M et al (2008) FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132:958–970PubMedGoogle Scholar
  38. 38.
    Goodson ML, Jonas BA, Privalsky ML (2005) Alternative mRNA splicing of SMRT creates functional diversity by generating corepressor isoforms with different affinities for different nuclear receptors. J Biol Chem 280(9):7493–503PubMedGoogle Scholar
  39. 39.
    Jepsen K et al (2007) SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450:415–419PubMedGoogle Scholar
  40. 40.
    Alenghat T et al (2008) Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456(7224):997–1000PubMedGoogle Scholar
  41. 41.
    Astapova I et al (2008) The nuclear corepressor, NCoR, regulates thyroid hormone action in vivo. Proc Natl Acad Sci USA 105(49):19544–9PubMedGoogle Scholar
  42. 42.
    Sutanto MM, Symons MS, Cohen RN (2007) SMRT recruitment by PPARgamma is mediated by specific residues located in its carboxy-terminal interacting domain. Mol Cell Endocrinol 267:138–143PubMedGoogle Scholar
  43. 43.
    Polly P et al (2000) VDR-Alien: a novel, DNA-selective vitamin D(3) receptor-corepressor partnership. FASEB J 14:1455–1463PubMedGoogle Scholar
  44. 44.
    Lykke-Andersen K et al (2003) Disruption of the COP9 signalosome Csn2 subunit in mice causes deficient cell proliferation, accumulation of p53 and cyclin E, and early embryonic death. Mol Cell Biol 23:6790–6797PubMedGoogle Scholar
  45. 45.
    Hatchell EC et al (2006) SLIRP, a small SRA binding protein, is a nuclear receptor corepressor. Mol Cell 22:657–668PubMedGoogle Scholar
  46. 46.
    Hsieh JC et al (2003) Physical and functional interaction between the vitamin D receptor and hairless corepressor, two proteins required for hair cycling. J Biol Chem 278:38665–38674PubMedGoogle Scholar
  47. 47.
    Miller J et al (2001) 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 117:612–617PubMedGoogle Scholar
  48. 48.
    Xie Z, Chang S, Oda Y, Bikle DD (2005) Hairless suppresses vitamin D receptor transactivation in human keratinocytes. Endocrinology 147(1):314–23PubMedGoogle Scholar
  49. 49.
    Scsucova S et al (2005) The repressor DREAM acts as a transcriptional activator on Vitamin D and retinoic acid response elements. Nucleic Acids Res 33:2269–2279PubMedGoogle Scholar
  50. 50.
    Fujiki R et al (2005) Ligand-induced transrepression by VDR through association of WSTF with acetylated histones. EMBO J 24:3881–3894PubMedGoogle Scholar
  51. 51.
    Kitagawa H et al (2003) The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell 113:905–917PubMedGoogle Scholar
  52. 52.
    Ding XF et al (1998) Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol Endocrinol 12:302–313PubMedGoogle Scholar
  53. 53.
    Eggert M et al (1995) A fraction enriched in a novel glucocorticoid receptor-interacting protein stimulates receptor-dependent transcription in vitro. J Biol Chem 270:30755–30759PubMedGoogle Scholar
  54. 54.
    Zhang J, Fondell JD (1999) Identification of mouse TRAP100: a transcriptional coregulatory factor for thyroid hormone and vitamin D receptors. Mol Endocrinol 13:1130–1140PubMedGoogle Scholar
  55. 55.
    Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG (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 95:7939–7944PubMedGoogle Scholar
  56. 56.
    Lee JW, Choi HS, Gyuris J, Brent R, Moore DD (1995) Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol Endocrinol 9:243–254PubMedGoogle Scholar
  57. 57.
    Zhang C et al (2003) Nuclear coactivator-62 kDa/Ski-interacting protein is a nuclear matrix-associated coactivator that may couple vitamin D receptor-mediated transcription and RNA splicing. J Biol Chem 278:35325–35336PubMedGoogle Scholar
  58. 58.
    Urahama N et al (2005) The role of transcriptional coactivator TRAP220 in myelomonocytic differentiation. Genes Cells 10:1127–1137PubMedGoogle Scholar
  59. 59.
    Ren Y et al (2000) Specific structural motifs determine TRAP220 interactions with nuclear hormone receptors. Mol Cell Biol 20:5433–5446PubMedGoogle Scholar
  60. 60.
    Teichert A et al (2009) Quantification of the Vitamin D Receptor-Coregulator Interaction (dagger). Biochemistry 48(7):1254–61Google Scholar
  61. 61.
    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 127:874–880PubMedGoogle Scholar
  62. 62.
    Lutz W, Kohno K, Kumar R (2001) The role of heat shock protein 70 in vitamin D receptor function. Biochem Biophys Res Commun 282:1211–1219PubMedGoogle Scholar
  63. 63.
    Guzey M, Takayama S, Reed JC (2000) BAG1L enhances trans-activation function of the vitamin D receptor. J Biol Chem 275:40749–40756PubMedGoogle Scholar
  64. 64.
    Bikle D, Teichert A, Hawker N, Xie Z, Oda Y (2007) Sequential regulation of keratinocyte differentiation by 1, 25(OH)2D3, VDR, and its coregulators. J Steroid Biochem Mol Biol 103:396–404PubMedGoogle Scholar
  65. 65.
    Blok LJ, de Ruiter PE, Brinkmann AO (1996) Androgen receptor phosphorylation. Endocr Res 22:197–219PubMedGoogle Scholar
  66. 66.
    Hilliard GMT, Cook RG, Weigel NL, Pike JW (1994) 1, 25-dihydroxyvitamin D3 modulates phosphorylation of serine 205 in the human vitamin D receptor: site-directed mutagenesis of this residue promotes alternative phosphorylation. Biochemistry 33:4300–4311PubMedGoogle Scholar
  67. 67.
    Hsieh JC et al (1991) Human vitamin D receptor is selectively phosphorylated by protein kinase C on serine 51, a residue crucial to its trans-activation function. Proc Natl Acad Sci USA 88:9315–9319PubMedGoogle Scholar
  68. 68.
    Macoritto M et al (2008) Phosphorylation of the human retinoid X receptor alpha at serine 260 impairs coactivator(s) recruitment and induces hormone resistance to multiple ligands. J Biol Chem 283:4943–4956PubMedGoogle Scholar
  69. 69.
    Arriagada G et al (2007) Phosphorylation at serine 208 of the 1[alpha], 25-dihydroxy vitamin D3 receptor modulates the interaction with transcriptional coactivators. J Steroid Biochem Mol Biol 103:425–429PubMedGoogle Scholar
  70. 70.
    Jurutka PW et al (1996) Human vitamin D receptor phosphorylation by casein kinase II at Ser-208 potentiates transcriptional activation. Proc Natl Acad Sci USA 93:3519–3524PubMedGoogle Scholar
  71. 71.
    Barletta F, Freedman LP, Christakos S (2002) Enhancement of VDR-mediated transcription by phosphorylation: correlation with increased interaction between the VDR and DRIP205, a subunit of the VDR-interacting protein coactivator complex. Mol Endocrinol 16:301–314PubMedGoogle Scholar
  72. 72.
    Carlberg C, Seuter S (2007) The vitamin D receptor. Dermatol Clin 25:515–523, viiiPubMedGoogle Scholar
  73. 73.
    Thompson PD et al (2002) Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements. Biochem Biophys Res Commun 299:730–738PubMedGoogle Scholar
  74. 74.
    Song CS et al (2006) An essential role of the CAAT/enhancer binding protein-alpha in the vitamin D-induced expression of the human steroid/bile acid-sulfotransferase (SULT2A1). Mol Endocrinol 20:795–808PubMedGoogle Scholar
  75. 75.
    Rosenfeld MG, Lunyak VV, Glass CK (2006) Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 20:1405–1428PubMedGoogle Scholar
  76. 76.
    Chen CD et al (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10:33–39PubMedGoogle Scholar
  77. 77.
    Murayama A, Kim MS, Yanagisawa J, Takeyama K, Kato S (2004) Transrepression by a liganded nuclear receptor via a bHLH activator through co-regulator switching. EMBO J 23:1598–1608PubMedGoogle Scholar
  78. 78.
    Fujiki R et al (2005) Ligand-induced transrepression by VDR through association of WSTF with acetylated histones. EMBO J 24:3881–3894PubMedGoogle Scholar
  79. 79.
    Kim MS et al (2007) 1Alpha, 25(OH)2D3-induced transrepression by vitamin D receptor through E-box-type elements in the human parathyroid hormone gene promoter. Mol Endocrinol 21:334–342PubMedGoogle Scholar
  80. 80.
    Turunen MM, Dunlop TW, Carlberg C, Vaisanen S (2007) Selective use of multiple vitamin D response elements underlies the 1 alpha, 25-dihydroxyvitamin D3-mediated negative regulation of the human CYP27B1 gene. Nucleic Acids Res 35:2734–2747PubMedGoogle Scholar
  81. 81.
    Song CS et al (2005) An essential role of the CAAT/enhancer binding protein-{alpha} in the vitamin D induced expression of the human steroid/bile acid-sulfotransferase (SULT2A1). Mol Endocrinol 20(4):795–808PubMedGoogle Scholar
  82. 82.
    Eeckhoute J, Carroll JS, Geistlinger TR, Torres-Arzayus MI, Brown M (2006) A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer. Genes Dev 20:2513–2526PubMedGoogle Scholar
  83. 83.
    Turner BM (1998) Histone acetylation as an epigenetic determinant of long-term transcriptional competence. Cell Mol Life Sci 54:21–31PubMedGoogle Scholar
  84. 84.
    Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080PubMedGoogle Scholar
  85. 85.
    Turner BM (2002) Cellular memory and the histone code. Cell 111:285–291PubMedGoogle Scholar
  86. 86.
    Hartman HB, Yu J, Alenghat T, Ishizuka T, Lazar MA (2005) The histone-binding code of nuclear receptor co-repressors matches the substrate specificity of histone deacetylase 3. EMBO Rep 6:445–451PubMedGoogle Scholar
  87. 87.
    Strahl BD et al (2001) Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1. Curr Biol 11:996–1000PubMedGoogle Scholar
  88. 88.
    Shogren-Knaak M et al (2006) Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311:844–847PubMedGoogle Scholar
  89. 89.
    Shi X et al (2006) ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442:96–99PubMedGoogle Scholar
  90. 90.
    Varambally S et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624–629PubMedGoogle Scholar
  91. 91.
    Yu J, Li Y, Ishizuka T, Guenther MG, Lazar MA (2003) A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation. EMBO J 22:3403–3410PubMedGoogle Scholar
  92. 92.
    Roux C et al (2008) New insights into the role of vitamin D and calcium in osteoporosis management: an expert roundtable discussion. Curr Med Res Opin 24:1363–1370PubMedGoogle Scholar
  93. 93.
    Dawson-Hughes B et al (2005) Estimates of optimal vitamin D status. Osteoporos Int 16:713–716PubMedGoogle Scholar
  94. 94.
    Yoshizawa T et al (1997) Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 16:391–396PubMedGoogle Scholar
  95. 95.
    Li YC et al (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 94:9831–9835PubMedGoogle Scholar
  96. 96.
    Van Cromphaut SJ et al (2001) Duodenal calcium absorption in vitamin D receptor-knockout mice: functional and molecular aspects. Proc Natl Acad Sci USA 98:13324–13329PubMedGoogle Scholar
  97. 97.
    Dontu G, Al Hajj M, Abdallah WM, Clarke MF, Wicha MS (2003) Stem cells in normal breast development and breast cancer. Cell Prolif 36(Suppl 1):59–72PubMedGoogle Scholar
  98. 98.
    Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850PubMedGoogle Scholar
  99. 99.
    Al Hajj M, Clarke MF (2004) Self-renewal and solid tumor stem cells. Oncogene 23:7274–7282PubMedGoogle Scholar
  100. 100.
    Al Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF (2004) Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 14:43–47PubMedGoogle Scholar
  101. 101.
    De Marzo AM, Nelson WG, Meeker AK, Coffey DS (1998) Stem cell features of benign and malignant prostate epithelial cells. J Urol 160:2381–2392PubMedGoogle Scholar
  102. 102.
    Huss WJ, Gray DR, Werdin ES, Funkhouser WK Jr, Smith GJ (2004) Evidence of ­pluripotent human prostate stem cells in a human prostate primary xenograft model. Prostate 60:77–90PubMedGoogle Scholar
  103. 103.
    Bikle DD, Gee E, Pillai S (1993) Regulation of keratinocyte growth, differentiation, and vitamin D metabolism by analogs of 1, 25-dihydroxyvitamin D. J Invest Dermatol 101:713–718PubMedGoogle Scholar
  104. 104.
    Reichrath J et al (1994) Hair follicle expression of 1, 25-dihydroxyvitamin D3 receptors during the murine hair cycle. Br J Dermatol 131:477–482PubMedGoogle Scholar
  105. 105.
    Sakai Y, Kishimoto J, Demay MB (2001) Metabolic and cellular analysis of alopecia in vitamin D receptor knockout mice. J Clin Invest 107:961–966PubMedGoogle Scholar
  106. 106.
    Palmer HG, Martinez D, Carmeliet G, Watt FM (2008) The vitamin D receptor is required for mouse hair cycle progression but not for maintenance of the epidermal stem cell compartment. J Invest Dermatol 128:2113–2117PubMedGoogle Scholar
  107. 107.
    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 282:10953–10962PubMedGoogle Scholar
  108. 108.
    Nam Y et al (2006) A novel missense mutation in the mouse hairless gene causes irreversible hair loss: genetic and molecular analyses of Hr m1Enu. Genomics 87:520–526PubMedGoogle Scholar
  109. 109.
    Bikle DD, Elalieh H, Chang S, Xie Z, Sundberg JP (2006) Development and progression of alopecia in the vitamin D receptor null mouse. J Cell Physiol 207:340–353PubMedGoogle Scholar
  110. 110.
    Beaudoin GM 3rd, Sisk JM, Coulombe PA, Thompson CC (2005) Hairless triggers reactivation of hair growth by promoting Wnt signaling. Proc Natl Acad Sci USA 102:14653–14658PubMedGoogle Scholar
  111. 111.
    Thompson CC, Sisk JM, Beaudoin GM 3rd (2006) Hairless and Wnt signaling: allies in epithelial stem cell differentiation. Cell Cycle 5:1913–1917PubMedGoogle Scholar
  112. 112.
    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:e1483PubMedGoogle Scholar
  113. 113.
    Zinser G, Packman K, Welsh J (2002) Vitamin D(3) receptor ablation alters mammary gland morphogenesis. Development 129:3067–3076PubMedGoogle Scholar
  114. 114.
    Zinser GM, Welsh J (2004) Accelerated mammary gland development during pregnancy and delayed postlactational involution in vitamin D3 receptor null mice. Mol Endocrinol 18:2208–2223PubMedGoogle Scholar
  115. 115.
    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 108:1083–1086PubMedGoogle Scholar
  116. 116.
    Miyaura C et al (1981) 1 alpha, 25-Dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells. Biochem Biophys Res Commun 102:937–943PubMedGoogle Scholar
  117. 117.
    Abe E et al (1981) Differentiation of mouse myeloid leukemia cells induced by 1 alpha, 25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 78:4990–4994PubMedGoogle Scholar
  118. 118.
    Palmer HG et al (2003) Genetic signatures of differentiation induced by 1alpha, 25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res 63:7799–7806PubMedGoogle Scholar
  119. 119.
    Koike M et al (1997) 19-nor-hexafluoride analogue of vitamin D3: a novel class of potent inhibitors of proliferation of human breast cell lines. Cancer Res 57:4545–4550PubMedGoogle Scholar
  120. 120.
    Campbell MJ, Elstner E, Holden S, Uskokovic M, Koeffler HP (1997) Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin. J Mol Endocrinol 19:15–27PubMedGoogle Scholar
  121. 121.
    Elstner E et al (1999) Novel 20-epi-vitamin D3 analog combined with 9-cis-retinoic acid markedly inhibits colony growth of prostate cancer cells. Prostate 40:141–149PubMedGoogle Scholar
  122. 122.
    Peehl DM et al (1994) Antiproliferative effects of 1, 25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res 54:805–810PubMedGoogle Scholar
  123. 123.
    Welsh J et al (2002) Impact of the Vitamin D3 receptor on growth-regulatory pathways in mammary gland and breast cancer. J Steroid Biochem Mol Biol 83:85–92PubMedGoogle Scholar
  124. 124.
    Colston KW, Berger U, Coombes RC (1989) Possible role for vitamin D in controlling breast cancer cell proliferation. Lancet 1:188–191PubMedGoogle Scholar
  125. 125.
    Colston K, Colston MJ, Fieldsteel AH, Feldman D (1982) 1, 25-dihydroxyvitamin D3 receptors in human epithelial cancer cell lines. Cancer Res 42:856–859PubMedGoogle Scholar
  126. 126.
    Eelen G et al (2004) Microarray analysis of 1alpha, 25-dihydroxyvitamin D3-treated MC3T3–E1 cells. J Steroid Biochem Mol Biol 89–90:405–407PubMedGoogle Scholar
  127. 127.
    Akutsu N et al (2001) Regulation of gene expression by 1alpha, 25-dihydroxyvitamin D3 and its analog EB1089 under growth-inhibitory conditions in squamous carcinoma cells. Mol Endocrinol 15:1127–1139PubMedGoogle Scholar
  128. 128.
    Wang TT et al (2005) Large-scale in silico and microarray-based identification of direct 1, 25-dihydroxyvitamin D3 target genes. Mol Endocrinol 19(11):2685–95PubMedGoogle Scholar
  129. 129.
    Liu M, Lee MH, Cohen M, Bommakanti M, Freedman LP (1996) Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev 10:142–153PubMedGoogle Scholar
  130. 130.
    Wang QM, Jones JB, Studzinski GP (1996) Cyclin-dependent kinase inhibitor p27 as a mediator of the G1-S phase block induced by 1, 25-dihydroxyvitamin D3 in HL60 cells. Cancer Res 56:264–267PubMedGoogle Scholar
  131. 131.
    Li P et al (2004) p27(Kip1) stabilization and G(1) arrest by 1, 25-dihydroxyvitamin D(3) in ovarian cancer cells mediated through down-regulation of cyclin E/cyclin-dependent kinase 2 and Skp1-Cullin-F-box protein/Skp2 ubiquitin ligase. J Biol Chem 279:25260–25267PubMedGoogle Scholar
  132. 132.
    Huang YC, Chen JY, Hung WC (2004) Vitamin D(3) receptor/Sp1 complex is required for the induction of p27(Kip1) expression by vitamin D(3). Oncogene 23(28):4856–61PubMedGoogle Scholar
  133. 133.
    Hengst L, Reed S (1996) Translational control of p27Kip1 accumulation during the cell cycle. Science 271:1861–1864PubMedGoogle Scholar
  134. 134.
    Jiang F, Li P, Fornace AJ Jr, Nicosia SV, Bai W (2003) G2/M arrest by 1, 25-dihydroxyvitamin D3 in ovarian cancer cells mediated through the induction of GADD45 via an exonic enhancer. J Biol Chem 278:48030–48040PubMedGoogle Scholar
  135. 135.
    Khanim FL et al (2004) Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells. Oncogene 23:6712–6725PubMedGoogle Scholar
  136. 136.
    Lubbert M et al (1991) Stable methylation patterns of MYC and other genes regulated during terminal myeloid differentiation. Leukemia 5:533–539PubMedGoogle Scholar
  137. 137.
    Koeffler HP (1983) Induction of differentiation of human acute myelogenous leukemia cells: therapeutic implications. Blood 62:709–721PubMedGoogle Scholar
  138. 138.
    Studzinski GP, Bhandal AK, Brelvi ZS (1986) Potentiation by 1-alpha, 25-dihydroxyvitamin D3 of cytotoxicity to HL-60 cells produced by cytarabine and hydroxyurea. J Natl Cancer Inst 76:641–648PubMedGoogle Scholar
  139. 139.
    Lin RJ et al (1998) Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391:811–814PubMedGoogle Scholar
  140. 140.
    Song G, Wang L (2008) Transcriptional mechanism for the paired miR-433 and miR-127 genes by nuclear receptors SHP and ERRgamma. Nucleic Acids Res 36:5727–5735PubMedGoogle Scholar
  141. 141.
    Shah YM et al (2007) Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation. Mol Cell Biol 27:4238–4247PubMedGoogle Scholar
  142. 142.
    Barbieri CE, Pietenpol JA (2006) p63 and epithelial biology. Exp Cell Res 312:695–706PubMedGoogle Scholar
  143. 143.
    Blackburn AC, Jerry DJ (2002) Knockout and transgenic mice of Trp53: what have we learned about p53 in breast cancer? Breast Cancer Res 4:101–111PubMedGoogle Scholar
  144. 144.
    Kommagani R, Caserta TM, Kadakia MP (2006) Identification of vitamin D receptor as a target of p63. Oncogene 25:3745–3751PubMedGoogle Scholar
  145. 145.
    Maruyama R et al (2006) Comparative genome analysis identifies the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation. Cancer Res 66:4574–4583PubMedGoogle Scholar
  146. 146.
    Lu J et al (2005) Transcriptional profiling of keratinocytes reveals a vitamin D-regulated epidermal differentiation network. J Invest Dermatol 124:778–785PubMedGoogle Scholar
  147. 147.
    Yang L, Yang J, Venkateswarlu S, Ko T, Brattain MG (2001) Autocrine TGFbeta signaling mediates vitamin D3 analog-induced growth inhibition in breast cells. J Cell Physiol 188:383–393PubMedGoogle Scholar
  148. 148.
    Wu Y, Craig TA, Lutz WH, Kumar R (1999) Identification of 1 alpha, 25-dihydroxyvitamin D3 response elements in the human transforming growth factor beta 2 gene. Biochemistry 38:2654–2660PubMedGoogle Scholar
  149. 149.
    Matilainen M, Malinen M, Saavalainen K, Carlberg C (2005) Regulation of multiple insulin-like growth factor binding protein genes by 1alpha, 25-dihydroxyvitamin D3. Nucleic Acids Res 33:5521–5532PubMedGoogle Scholar
  150. 150.
    Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604PubMedGoogle Scholar
  151. 151.
    Lee D et al (2002) SWI/SNF complex interacts with tumor suppressor p53 and is necessary for the activation of p53-mediated transcription. J Biol Chem 277:22330–22337PubMedGoogle Scholar
  152. 152.
    Wilkinson DS et al (2005) A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and transcription repression of the alpha-fetoprotein gene. Mol Cell Biol 25:1200–1212PubMedGoogle Scholar
  153. 153.
    Szeto FL et al (2007) Involvement of the vitamin D receptor in the regulation of NF-[kappa]B activity in fibroblasts. J Steroid Biochem Mol Biol 103:563–566PubMedGoogle Scholar
  154. 154.
    Froicu M, Cantorna M (2007) Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol 8:5PubMedGoogle Scholar
  155. 155.
    Gombart AF, Borregaard N, Koeffler HP (2005) Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1, 25-dihydroxyvitamin D3. FASEB J 19:1067–1077PubMedGoogle Scholar
  156. 156.
    Wan T-T et al (2004) Cutting edge: 1, 25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173:2909–2912Google Scholar
  157. 157.
    Mallbris LED, Sundblad L, Granath F, Stahle M (2005) UVB Upregulates the antimicrobial protein hCAP18 mRNA in human skin. J Investig Dermatol 125:1072–1074PubMedGoogle Scholar
  158. 158.
    Zasloff M (2005) Sunlight, vitamin D, and the innate immune defenses of the human skin. J Investig Dermatol 125:xvi–xviiPubMedGoogle Scholar
  159. 159.
    Quigley DA et al (2009) Genetic architecture of mouse skin inflammation and tumour susceptibility. Nature 458(7237):505–8PubMedGoogle Scholar
  160. 160.
    Blutt SE, McDonnell TJ, Polek TC, Weigel NL (2000) Calcitriol-induced apoptosis in LNCaP cells is blocked by overexpression of Bcl-2. Endocrinology 141:10–17PubMedGoogle Scholar
  161. 161.
    Mathiasen I, Lademann U, Jaattela M (1999) Apoptosis induced by vitamin D compounds in breast cancer cells is inhibited by Bcl-2 but does not involve known caspases or p53. Cancer Res 59:4848–4856PubMedGoogle Scholar
  162. 162.
    Song H et al (2003) Vitamin D(3) up-regulating protein 1 (VDUP1) antisense DNA regulates tumorigenicity and melanogenesis of murine melanoma cells via regulating the expression of fas ligand and reactive oxygen species. Immunol Lett 86:235–247PubMedGoogle Scholar
  163. 163.
    Han SH et al (2003) VDUP1 upregulated by TGF-beta1 and 1, 25-dihydorxyvitamin D3 inhibits tumor cell growth by blocking cell-cycle progression. Oncogene 22:4035–4046PubMedGoogle Scholar
  164. 164.
    Albertson DG et al (2000) Quantitative mapping of amplicon structure by array CGH ­identifies CYP24 as a candidate oncogene. Nat Genet 25:144–146PubMedGoogle Scholar
  165. 165.
    Townsend K et al (2005) Autocrine metabolism of vitamin D in normal and malignant breast tissue. Clin Cancer Res 11:3579–3586PubMedGoogle Scholar
  166. 166.
    Abedin SA et al (2009) Elevated NCOR1 disrupts a network of dietary-sensing nuclear receptors in bladder cancer cells. Carcinogenesis 30(3):449–56PubMedGoogle Scholar
  167. 167.
    Menezes RJ et al (2008) Vitamin D receptor expression in normal, premalignant, and ­malignant human lung tissue. Cancer Epidemiol Biomarkers Prev 17:1104–1110PubMedGoogle Scholar
  168. 168.
    Pendas-Franco N et al (2008) DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1alpha, 25-dihydroxyvitamin D3. Oncogene 27:4467–4477PubMedGoogle Scholar
  169. 169.
    Palmer HG et al (2004) The transcription factor SNAIL represses vitamin D receptor ­expression and responsiveness in human colon cancer. Nat Med 10:917–919PubMedGoogle Scholar
  170. 170.
    Palmer HG et al (2001) 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 154:369–387PubMedGoogle Scholar
  171. 171.
    Shah S et al (2006) The molecular basis of vitamin D receptor and beta-catenin crossregulation. Mol Cell 21:799–809PubMedGoogle Scholar
  172. 172.
    Miller CW, Morosetti R, Campbell MJ, Mendoza S, Koeffler HP (1997) Integrity of the 1, 25-dihydroxyvitamin D3 receptor in bone, lung, and other cancers. Mol Carcinog 19:254–257PubMedGoogle Scholar
  173. 173.
    Guy M, Lowe LC, Bretherton-Watt D, Mansi JL, Colston KW (2003) Approaches to evaluating the association of vitamin D receptor gene polymorphisms with breast cancer risk. Recent Results Cancer Res 164:43–54PubMedGoogle Scholar
  174. 174.
    John EM, Schwartz GG, Koo J, Van Den BD, Ingles SA (2005) Sun exposure, vitamin D receptor gene polymorphisms, and risk of advanced prostate cancer. Cancer Res 65:5470–5479PubMedGoogle Scholar
  175. 175.
    Ingles SA et al (1998) Association of prostate cancer with vitamin D receptor haplotypes in African-Americans. Cancer Res 58:1620–1623PubMedGoogle Scholar
  176. 176.
    Ma J et al (1998) Vitamin D receptor polymorphisms, circulating vitamin D metabolites, and risk of prostate cancer in United States physicians. Cancer Epidemiol Biomarkers Prev 7:385–390PubMedGoogle Scholar
  177. 177.
    Gorlach M, Burd CG, Dreyfuss G (1994) The mRNA poly(A)-binding protein: localization, abundance, and RNA-binding specificity. Exp Cell Res 211:400–407PubMedGoogle Scholar
  178. 178.
    Kim JG et al (2003) Association between vitamin D receptor gene haplotypes and bone mass in postmenopausal Korean women. Am J Obstet Gynecol 189:1234–1240PubMedGoogle Scholar
  179. 179.
    Kuraishi T, Sun Y, Aoki F, Imakawa K, Sakai S (2000) The poly(A) tail length of casein mRNA in the lactating mammary gland changes depending upon the accumulation and removal of milk. Biochem J 347:579–583PubMedGoogle Scholar
  180. 180.
    Schondorf T et al (2003) Association of the vitamin D receptor genotype with bone metastases in breast cancer patients. Oncology 64:154–159PubMedGoogle Scholar
  181. 181.
    Lundin AC, Soderkvist P, Eriksson B, Bergman-Jungestrom M, Wingren S (1999) Association of breast cancer progression with a vitamin D receptor gene polymorphism. South-East Sweden Breast Cancer Group. Cancer Res 59:2332–2334PubMedGoogle Scholar
  182. 182.
    Guy M et al (2004) Vitamin d receptor gene polymorphisms and breast cancer risk. Clin Cancer Res 10:5472–5481PubMedGoogle Scholar
  183. 183.
    Ntais C, Polycarpou A, Ioannidis JP (2003) Vitamin D receptor gene polymorphisms and risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 12:1395–1402PubMedGoogle Scholar
  184. 184.
    Rashid SF et al (2001) Synergistic growth inhibition of prostate cancer cells by 1 alpha, 25 Dihydroxyvitamin D(3) and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A. Oncogene 20:1860–1872PubMedGoogle Scholar
  185. 185.
    Campbell MJ, Gombart AF, Kwok SH, Park S, Koeffler HP (2000) The anti-proliferative effects of 1alpha, 25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression. Oncogene 19:5091–5097PubMedGoogle Scholar
  186. 186.
    Miller GJ, Stapleton GE, Hedlund TE, Moffat KA (1995) Vitamin D receptor expression, 24-hydroxylase activity, and inhibition of growth by 1alpha, 25-dihydroxyvitamin D3 in seven human prostatic carcinoma cell lines. Clin Cancer Res 1:997–1003PubMedGoogle Scholar
  187. 187.
    Rashid SF, Mountford JC, Gombart AF, Campbell MJ (2001) 1alpha, 25-dihydroxyvitamin D(3) displays divergent growth effects in both normal and malignant cells. Steroids 66:433–440PubMedGoogle Scholar
  188. 188.
    Campbell MJ, Adorini L (2006) The vitamin D receptor as a therapeutic target. Expert Opin Ther Targets 10:735–748PubMedGoogle Scholar
  189. 189.
    Battaglia S, Maguire O, Thorne JL, Hornung LB, Doig CL, Liu S, Sucheston LE, Bianchi A, Khanim F, Gommersall LM, Coulter HS, Rakha S, Giddings I, O’Neill LP, Cooper CS, McCabe CJ, Bunce CM, Campbell MJ (2010) Elevated NCOR1 disrupts PPAR{alpha}/{gamma} signaling in prostate cancer and forms a targetable epigenetic lesion. Carcinogenesis 31(9):1650–60Google Scholar
  190. 190.
    Kim JY, Son YL, Lee YC (2008) Involvement of SMRT Corepressor in Transcriptional Repression by the Vitamin D Receptor. Mol Endocrinol 23(2):251–64PubMedGoogle Scholar
  191. 191.
    Ting HJ, Bao BY, Reeder JE, Messing EM, Lee YF (2007) Increased expression of ­corepressors in aggressive androgen-independent prostate cancer cells results in loss of 1alpha, 25-dihydroxyvitamin D3 responsiveness. Mol Cancer Res 5:967–980PubMedGoogle Scholar
  192. 192.
    Banwell CM et al (2006) Altered nuclear receptor corepressor expression attenuates vitamin D receptor signaling in breast cancer cells. Clin Cancer Res 12:2004–2013PubMedGoogle Scholar
  193. 193.
    Makishima M et al (2002) Vitamin D receptor as an intestinal bile acid sensor. Science 296:1313–1316PubMedGoogle Scholar
  194. 194.
    Banwell CM, O’Neill LP, Uskokovic MR, Campbell MJ (2004) Targeting 1alpha, 25-dihydroxyvitamin D3 antiproliferative insensitivity in breast cancer cells by co-treatment with histone deacetylation inhibitors. J Steroid Biochem Mol Biol 89–90:245–249PubMedGoogle Scholar
  195. 195.
    Tavera-Mendoza LE et al (2008) Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist. Proc Natl Acad Sci USA 105:8250–8255PubMedGoogle Scholar
  196. 196.
    Costa EM, Feldman D (1987) Modulation of 1, 25-dihydroxyvitamin D3 receptor binding and action by sodium butyrate in cultured pig kidney cells (LLC-PK1). J Bone Miner Res 2:151–159PubMedGoogle Scholar
  197. 197.
    Gaschott T, Stein J (2003) Short-chain fatty acids and colon cancer cells: the vitamin D receptor–butyrate connection. Recent Results Cancer Res 164:247–257PubMedGoogle Scholar
  198. 198.
    Daniel C, Schroder O, Zahn N, Gaschott T, Stein J (2004) p38 MAPK signaling pathway is involved in butyrate-induced vitamin D receptor expression. Biochem Biophys Res Commun 324:1220–1226PubMedGoogle Scholar
  199. 199.
    Chen JS, Faller DV, Spanjaard RA (2003) Short-chain fatty acid inhibitors of histone deacetylases: promising anticancer therapeutics? Curr Cancer Drug Targets 3:219–236PubMedGoogle Scholar
  200. 200.
    Gaschott T, Werz O, Steinmeyer A, Steinhilber D, Stein J (2001) Butyrate-induced differentiation of Caco-2 cells is mediated by vitamin D receptor. Biochem Biophys Res Commun 288:690–696PubMedGoogle Scholar
  201. 201.
    Tanaka Y, Bush KK, Klauck TM, Higgins PJ (1989) Enhancement of butyrate-induced ­differentiation of HT-29 human colon carcinoma cells by 1, 25-dihydroxyvitamin D3. Biochem Pharmacol 38:3859–3865PubMedGoogle Scholar
  202. 202.
    Krasowski MD, Yasuda K, Hagey LR, Schuetz EG (2005) Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors). Nucl Recept 3:2PubMedGoogle Scholar
  203. 203.
    Bookout AL et al (2006) Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126:789–799PubMedGoogle Scholar
  204. 204.
    Carlberg C, Dunlop TW (2006) An integrated biological approach to nuclear receptor signaling in physiological control and disease. Crit Rev Eukaryot Gene Expr 16:1–22PubMedGoogle Scholar
  205. 205.
    Adorini L, Daniel KC, Penna G (2006) Vitamin D receptor agonists, cancer and the immune system: an intricate relationship. Curr Top Med Chem 6:1297–1301PubMedGoogle Scholar
  206. 206.
    Evans RM (2005) The nuclear receptor superfamily: a rosetta stone for physiology. Mol Endocrinol 19:1429–1438PubMedGoogle Scholar
  207. 207.
    Westerhoff HV, Palsson BO (2004) The evolution of molecular biology into systems biology. Nat Biotechnol 22:1249–1252PubMedGoogle Scholar
  208. 208.
    Muller M, Kersten S (2003) Nutrigenomics: goals and strategies. Nat Rev Genet 4:315–322PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Pharmacology & TherapeuticsRoswell Park Cancer InstituteNYUSA

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