title: Glucocorticoid regulation of the vitamin D receptor.
abstract: Many studies indicate calcitriol has potent anti-tumor activity in different types of cancers. However, high levels of vitamin D can produce hypercalcemia in some patients. Glucocorticoids are used to ameliorate hypercalcemia and to enhance calcitriol anti-tumor activity. Calcitriol in combination with the glucocorticoid dexamethasone (Dex) increased vitamin D receptor (VDR) protein levels and ligand binding in squamous cell carcinoma VII (SCC). In this study we found that both calcitriol and Dex induce VDR- and glucocorticoid receptor (GR)-mediated transcription respectively, indicating both hormone receptors are active in SCC. Pre-treatment with Dex increases VDR-mediated transcription at the human CYP24A1 promoter. Whereas, pre-treatment with other steroid hormones, including dihydrotestosterone and R1881, has no effect on VDR-mediated transcription. Real-time PCR indicates treatment with Dex increases Vdr transcripts in a time-dependent manner, suggesting Dex may directly regulate expression of Vdr. Numerous putative glucocorticoid response elements (GREs) were found in the Vdr gene. Chromatin immuno-precipitation (ChIP) assay demonstrated GR binding at several putative GREs located within the mouse Vdr gene. However, none of the putative GREs studied increase GR-mediated transcription in luciferase reporter assays. In an attempt to identify the response element responsible for Vdr transcript regulation, future studies will continue to analyze newly identified GREs more distal from the Vdr gene promoter.
authors.affiliation: Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY 14214, United States.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Hidalgo
authors.forename: Donald L
authors.initials: DL
authors.lastname: Trump
authors.forename: Candace S
authors.initials: CS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003907:Dexamethasone / Q000378:metabolism; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D006934:Hypercalcemia / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000378:metabolism*; D020218:Response Elements; D013250:Steroid Hydroxylases / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D005938:Glucocorticoids; D018167:Receptors, Calcitriol; D003907:Dexamethasone; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol
references.citation: Biochem Biophys Res Commun. 1993 Sep 30;195(3):1345-53
references.pmid: 8216267
references.citation: Cancer Res. 2009 Feb 1;69(3):967-75
references.pmid: 19141646
references.citation: Mol Endocrinol. 2002 Jun;16(6):1269-79
references.pmid: 12040014
references.citation: Clin Cancer Res. 2001 Dec;7(12):4164-73
references.pmid: 11751517
references.citation: Oncogene. 2007 Mar 22;26(13):1885-96
references.pmid: 17016446
references.citation: J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):425-9
references.pmid: 17368182
references.citation: Arch Biochem Biophys. 2000 May 15;377(2):273-83
references.pmid: 10845704
references.citation: J Endocrinol. 2000 Mar;164(3):339-48
references.pmid: 10694374
references.citation: J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):352-6
references.pmid: 17240138
references.citation: J Natl Cancer Inst. 1998 Jan 21;90(2):134-41
references.pmid: 9450573
references.citation: J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):768-70
references.pmid: 17368191
references.citation: Mol Endocrinol. 2010 Jan;24(1):128-47
references.pmid: 19897601
references.citation: Biochem Biophys Res Commun. 1982 Apr 29;105(4):1590-6
references.pmid: 6285911
references.citation: J Biol Chem. 1993 Jul 15;268(20):15118-26
references.pmid: 8392065
references.citation: Exp Physiol. 2009 Jan;94(1):138-51
references.pmid: 18931045
references.citation: Am J Physiol Endocrinol Metab. 2006 Feb;290(2):E299-307
references.pmid: 16219669
references.citation: Nat Rev Cancer. 2007 Sep;7(9):684-700
references.pmid: 17721433
references.citation: Oncology. 2006;70(6):447-57
references.pmid: 17237620
references.citation: Endocrinology. 2000 Aug;141(8):2829-36
references.pmid: 10919269
references.citation: Nat Genet. 1997 Aug;16(4):391-6
references.pmid: 9241280
references.citation: Life Sci. 2009 Jul 17;85(3-4):146-52
references.pmid: 19490920
references.citation: Int J Obes (Lond). 2008 Aug;32(8):1305-11
references.pmid: 18427562
references.citation: Carcinogenesis. 2001 Sep;22(9):1429-35
references.pmid: 11532865
references.citation: J Nutr. 1996 Apr;126(4 Suppl):1159S-64S
references.pmid: 8642450
references.citation: Int J Cancer. 2009 Sep 15;125(6):1328-33
references.pmid: 19437538
references.citation: Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9315-9
references.pmid: 1656468
references.citation: Cancer. 2006 May 15;106(10):2136-42
references.pmid: 16598750