This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jurutka, P. W. Articles by Haussler, M. R. Search for Related Content PubMed PubMed Citation Articles by Jurutka, P. W. Articles by Haussler, M. R.

The Polymorphic N Terminus in Human Vitamin D Receptor Isoforms Influences Transcriptional Activity by Modulating Interaction with Transcription Factor IIB

Department of Biochemistry College of Medicine University of Arizona Tucson, Arizona 85724

The human vitamin D receptor (hVDR) is a ligand-regulated transcription factor that mediates the actions of the 1,25-dihydroxyvitamin D₃ hormone to effect bone mineral homeostasis. Employing mutational analysis, we characterized Arg-18/Arg-22, hVDR residues immediately N-terminal of the first DNA binding zinc finger, as vital for contact with human basal transcription factor IIB (TFIIB). Alteration of either of these basic amino acids to alanine also compromised hVDR transcriptional activity. In contrast, an artificial hVDR truncation devoid of the first 12 residues displayed both enhanced interaction with TFIIB and transactivation. Similarly, a natural polymorphic variant of hVDR, termed F/M4 (missing a FokI restriction site), which lacks only the first three amino acids (including Glu-2), interacted more efficiently with TFIIB and also possessed elevated transcriptional activity compared with the full-length (f/M1) receptor. It is concluded that the functioning of positively charged Arg-18/Arg-22 as part of an hVDR docking site for TFIIB is influenced by the composition of the adjacent polymorphic N terminus. Increased transactivation by the F/M4 neomorphic hVDR is hypothesized to result from its demonstrated enhanced association with TFIIB. This proposal is supported by the observed conversion of f/M1 hVDR activity to that of F/M4 hVDR, either by overexpression of TFIIB or neutralization of the acidic Glu-2 by replacement with alanine in f/M1 hVDR. Because the f VDR genotype has been associated with lower bone mineral density in diverse populations, one factor contributing to a genetic predisposition to osteoporosis may be the F/f polymorphism that dictates VDR isoforms with differential TFIIB interaction.

This article has been cited by other articles:

				A.-L. Ponsonby, A. Pezic, J. Ellis, R. Morley, F. Cameron, J. Carlin, and T. Dwyer Variation in Associations between Allelic Variants of the Vitamin D Receptor Gene and Onset of Type 1 Diabetes Mellitus by Ambient Winter Ultraviolet Radiation Levels: A Meta-Regression Analysis Am. J. Epidemiol., August 15, 2008; 168(4): 358 - 365. [Abstract] [Full Text] [PDF]

				C. D Davis Vitamin D and cancer: current dilemmas and future research needs Am. J. Clinical Nutrition, August 1, 2008; 88(2): 565S - 569S. [Abstract] [Full Text] [PDF]

				G. Lurie, L. R. Wilkens, P. J. Thompson, K. E. McDuffie, M. E. Carney, K. Y. Terada, and M. T. Goodman Vitamin D Receptor Gene Polymorphisms and Epithelial Ovarian Cancer Risk Cancer Epidemiol. Biomarkers Prev., December 1, 2007; 16(12): 2566 - 2571. [Abstract] [Full Text] [PDF]

				M. S. Cicek, X. Liu, F. R. Schumacher, G. Casey, and J. S. Witte Vitamin D Receptor Genotypes/Haplotypes and Prostate Cancer Risk Cancer Epidemiol. Biomarkers Prev., December 1, 2006; 15(12): 2549 - 2552. [Abstract] [Full Text] [PDF]

				E. T. Jacobs, M. R. Haussler, and M. E. Martinez Vitamin D Activity and Colorectal Neoplasia: A Pathway Approach to Epidemiologic Studies Cancer Epidemiol. Biomarkers Prev., September 1, 2005; 14(9): 2061 - 2063. [Full Text] [PDF]

				M. J. Taverna, J.-L. Selam, and G. Slama Association between a Protein Polymorphism in the Start Codon of the Vitamin D Receptor Gene and Severe Diabetic Retinopathy in C-Peptide-Negative Type 1 Diabetes J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4803 - 4808. [Abstract] [Full Text] [PDF]

				K. M Rabon-Stith, J. M Hagberg, D. A Phares, M. C Kostek, M. J Delmonico, S. M Roth, R. E Ferrell, J. M Conway, A. S Ryan, and B. F Hurley Vitamin D receptor FokI genotype influences bone mineral density response to strength training, but not aerobic training Exp Physiol, July 1, 2005; 90(4): 653 - 661. [Abstract] [Full Text] [PDF]

				K. Skorija, M. Cox, J. M. Sisk, D. R. Dowd, P. N. MacDonald, C. C. Thompson, and M. B. Demay Ligand-Independent Actions of the Vitamin D Receptor Maintain Hair Follicle Homeostasis Mol. Endocrinol., April 1, 2005; 19(4): 855 - 862. [Abstract] [Full Text] [PDF]

				N. Morrison Commentary: Vitamin D receptor polymorphism and bone mineral density: effect size in Caucasians means detection is uncertain in small studies Int. J. Epidemiol., October 1, 2004; 33(5): 989 - 994. [Full Text] [PDF]

				I. Oakley-Girvan, D. Feldman, T. R. Eccleshall, R. P. Gallagher, A. H. Wu, L. N. Kolonel, J. Halpern, R. R. Balise, D. W. West, R. S. Paffenbarger Jr., et al. Risk of Early-Onset Prostate Cancer in Relation to Germ Line Polymorphisms of the Vitamin D Receptor Cancer Epidemiol. Biomarkers Prev., August 1, 2004; 13(8): 1325 - 1330. [Abstract] [Full Text] [PDF]

				L. Soldati, D. Adamo, C. Bianchin, T. Arcidiacono, A. Terranegra, M. L. Bianchi, S. Mora, D. Cusi, and G. Vezzoli Vitamin D Receptor mRNA Measured in Leukocytes with the TaqMan Fluorogenic Detection System: Effect of Calcitriol Administration Clin. Chem., August 1, 2004; 50(8): 1315 - 1321. [Abstract] [Full Text] [PDF]

				S. M. Roth, J. M. Zmuda, J. A. Cauley, P. R. Shea, and R. E. Ferrell Vitamin D Receptor Genotype Is Associated With Fat-Free Mass and Sarcopenia in Elderly Men J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2004; 59(1): B10 - 15. [Abstract] [Full Text] [PDF]

				E. T. Jacobs, M. E. Martinez, and D. S. Alberts Research and Public Health Implications of the Intricate Relationship Between Calcium and Vitamin D in the Prevention of Colorectal Neoplasia J Natl Cancer Inst, December 3, 2003; 95(23): 1736 - 1737. [Full Text] [PDF]

				D. J. Bettoun, T. P. Burris, K. A. Houck, D. W. Buck II, K. R. Stayrook, B. Khalifa, J. Lu, W. W. Chin, and S. Nagpal Retinoid X Receptor Is a Nonsilent Major Contributor to Vitamin D Receptor-Mediated Transcriptional Activation Mol. Endocrinol., November 1, 2003; 17(11): 2320 - 2328. [Abstract] [Full Text] [PDF]

				J.-C. Hsieh, G. K. Whitfield, P. W. Jurutka, C. A. Haussler, M. L. Thatcher, P. D. Thompson, H. T. L. Dang, M. A. Galligan, A. K. Oza, and M. R. Haussler Two Basic Amino Acids C-Terminal of the Proximal Box Specify Functional Binding of the Vitamin D Receptor to Its Rat Osteocalcin Deoxyribonucleic Acid- Responsive Element Endocrinology, November 1, 2003; 144(11): 5065 - 5080. [Abstract] [Full Text] [PDF]

				J.-C. Hsieh, J. M. Sisk, P. W. Jurutka, C. A. Haussler, S. A. Slater, M. R. Haussler, and C. C. Thompson Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling J. Biol. Chem., October 3, 2003; 278(40): 38665 - 38674. [Abstract] [Full Text] [PDF]

				D. M. Peehl, A. V. Krishnan, and D. Feldman Pathways Mediating the Growth-Inhibitory Actions of Vitamin D in Prostate Cancer J. Nutr., July 1, 2003; 133(7): 2461S - 2469. [Abstract] [Full Text] [PDF]

				G. K. Whitfield, H. T. L. Dang, S. F. Schluter, R. M. Bernstein, T. Bunag, L. A. Manzon, G. Hsieh, C. Encinas Dominguez, J. H. Youson, M. R. Haussler, et al. Cloning of a Functional Vitamin D Receptor from the Lamprey (Petromyzon marinus), an Ancient Vertebrate Lacking a Calcified Skeleton and Teeth Endocrinology, June 1, 2003; 144(6): 2704 - 2716. [Abstract] [Full Text] [PDF]

				H.-L. Wong, A. Seow, K. Arakawa, H.-P. Lee, M. C. Yu, and S. A. Ingles Vitamin D receptor start codon polymorphism and colorectal cancer risk: effect modification by dietary calcium and fat in Singapore Chinese Carcinogenesis, June 1, 2003; 24(6): 1091 - 1095. [Abstract] [Full Text] [PDF]

				A. L. M. Sutton and P. N. MacDonald Vitamin D: More Than a "Bone-a-Fide" Hormone Mol. Endocrinol., May 1, 2003; 17(5): 777 - 791. [Abstract] [Full Text] [PDF]

				J. B. Barry, G. M. Leong, W. B. Church, L. L. Issa, J. A. Eisman, and E. M. Gardiner Interactions of SKIP/NCoA-62, TFIIB, and Retinoid X Receptor with Vitamin D Receptor Helix H10 Residues J. Biol. Chem., February 28, 2003; 278(10): 8224 - 8228. [Abstract] [Full Text] [PDF]

				Y. Xu, A. Shibata, J. E. McNeal, T. A. Stamey, D. Feldman, and D. M. Peehl Vitamin D Receptor Start Codon Polymorphism (FokI) and Prostate Cancer Progression Cancer Epidemiol. Biomarkers Prev., January 1, 2003; 12(1): 23 - 27. [Abstract] [Full Text] [PDF]

				O. Nakamura, T. Ishii, Y. Ando, H. Amagai, M. Oto, T. Imafuji, and K. Tokuyama Potential role of vitamin D receptor gene polymorphism in determining bone phenotype in young male athletes J Appl Physiol, December 1, 2002; 93(6): 1973 - 1979. [Abstract] [Full Text] [PDF]

				B.-W. Ogunkolade, B. J. Boucher, J. M. Prahl, S. A. Bustin, J. M. Burrin, K. Noonan, B. V. North, N. Mannan, M. F. McDermott, H. F. DeLuca, et al. Vitamin D Receptor (VDR) mRNA and VDR Protein Levels in Relation to Vitamin D Status, Insulin Secretory Capacity, and VDR Genotype in Bangladeshi Asians Diabetes, July 1, 2002; 51(7): 2294 - 2300. [Abstract] [Full Text] [PDF]

				R. Metivier, G. Penot, G. Flouriot, and F. Pakdel Synergism Between ER{alpha} Transactivation Function 1 (AF-1) and AF-2 Mediated by Steroid Receptor Coactivator Protein-1: Requirement for the AF-1 {alpha}-Helical Core and for a Direct Interaction Between the N- and C-Terminal Domains Mol. Endocrinol., November 1, 2001; 15(11): 1953 - 1970. [Abstract] [Full Text] [PDF]

				K. L. Sunn, T.-A. Cock, L. A. Crofts, J. A. Eisman, and E. M. Gardiner Novel N-Terminal Variant of Human VDR Mol. Endocrinol., September 1, 2001; 15(9): 1599 - 1609. [Abstract] [Full Text] [PDF]

				A. L. Boskey Musculoskeletal Disorders and Orthopedic Conditions JAMA, February 7, 2001; 285(5): 619 - 623. [Abstract] [Full Text] [PDF]

				S. A. Gardezi, C. Nguyen, P. J. Malloy, G. H. Posner, D. Feldman, and S. Peleg A Rationale for Treatment of Hereditary Vitamin D-resistant Rickets with Analogs of 1alpha ,25-Dihydroxyvitamin D3 J. Biol. Chem., July 27, 2001; 276(31): 29148 - 29156. [Abstract] [Full Text] [PDF]