Abstract

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the accepted hormonal form of vitamin D which facilitates calcium and phosphorus homeostasis by acting on intestinal mineral absorption and bone remodeling. Recent evidence also implicates 1,25(OH)2D3 in normal hematopoiesis and cell differentiation. The proposed study will focus on elucidating the biochemical mechanism of 1,25(OH)2D3 action in a variety of target cells. Using monoclonal antibody we plan to further characterize the molecular properties of the 1,25(OH)2D3 receptor protein and prove that it is an obligatory mediator of the hormone's action. We will also study receptor modulation during target cell differentiation and analyze its binding to putative promotor regions of vitamin D regulated genes. The functions of 1,25(OH)2D3 in bone will be examined at the level of differentiating chondrocytes, osteoblasts, and osteoclast precursor cells. Another biological action of 1,25(OH)2D3, the induction of its catabolism via C-24 oxidation, will be investigated in cultured kidney cells. Biochemical details of the hormone's functions which may involve intracellular calcium and protein kinase C as well as nuclear protein modification and altered gene expression will be delineated. Finally, we will probe the regulation of cell growth and differentiation in normal and tumor cells by 1,25(OH)2D3. These basic studies will be complemented with measurements of 1,25(OH)2D3 receptor levels in patients with crush fracture osteoporosis, idiopathic hypercalciuria, osteogenic sarcoma and myelogenous leukemia. Our findings should not only reveal some of the early molecular events in the action of vitamin D, but they may add to our understanding of the pathophysiology and treatment of metabolic and malignant bone diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR015781-15
Application #
3154842
Study Section
General Medicine B Study Section (GMB)
Project Start
1975-01-01
Project End
1989-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
15
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722

  Publications

Jurutka, P W; Remus, L S; Whitfield, G K et al. (2000) The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol 14:401-20
Thompson, P D; Jurutka, P W; Haussler, C A et al. (1998) Heterodimeric DNA binding by the vitamin D receptor and retinoid X receptors is enhanced by 1,25-dihydroxyvitamin D3 and inhibited by 9-cis-retinoic acid. Evidence for allosteric receptor interactions. J Biol Chem 273:8483-91
Haussler, M R; Haussler, C A; Jurutka, P W et al. (1997) The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J Endocrinol 154 Suppl:S57-73
Jurutka, P W; Hsieh, J C; Remus, L S et al. (1997) Mutations in the 1,25-dihydroxyvitamin D3 receptor identifying C-terminal amino acids required for transcriptional activation that are functionally dissociated from hormone binding, heterodimeric DNA binding, and interaction with basal transcription facto J Biol Chem 272:14592-9
Whitfield, G K; Selznick, S H; Haussler, C A et al. (1996) Vitamin D receptors from patients with resistance to 1,25-dihydroxyvitamin D3: point mutations confer reduced transactivation in response to ligand and impaired interaction with the retinoid X receptor heterodimeric partner. Mol Endocrinol 10:1617-31
Jurutka, P W; Hsieh, J C; Nakajima, S et al. (1996) Human vitamin D receptor phosphorylation by casein kinase II at Ser-208 potentiates transcriptional activation. Proc Natl Acad Sci U S A 93:3519-24
Nakajima, S; Hsieh, J C; Jurutka, P et al. (1996) Examination of the potential functional role of conserved cysteine residues in the hormone binding domain of the human 1,25-dihydroxyvitamin D3 receptor. J Biol Chem 271:5143-9
Ray, R; Swamy, N; MacDonald, P N et al. (1996) Affinity labeling of the 1 alpha,25-dihydroxyvitamin D3 receptor. J Biol Chem 271:2012-7
Hsieh, J C; Jurutka, P W; Selznick, S H et al. (1995) The T-box near the zinc fingers of the human vitamin D receptor is required for heterodimeric DNA binding and transactivation. Biochem Biophys Res Commun 215:1-7
Haussler, M R; Jurutka, P W; Hsieh, J C et al. (1995) New understanding of the molecular mechanism of receptor-mediated genomic actions of the vitamin D hormone. Bone 17:33S-38S

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