| The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. | |
| | |
MedLine Citation:
|
PMID: 10707958 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
P W Jurutka; L S Remus; G K Whitfield; P D Thompson; J C Hsieh; H Zitzer; P Tavakkoli; M A Galligan; H T Dang; C A Haussler; M R Haussler |
Related Documents
:
|
8438978 - A work-site nutrition intervention: its effects on the consumption of cancer-related nu... 515958 - Role of vitamin e in the etiology of spontaneous hemorrhagic necrosis of the central ne... 16251308 - A class of pantothenic acid analogs inhibits plasmodium falciparum pantothenate kinase ... 2903228 - Interaction of vitamin e and its model compounds with unsaturated fatty acids in homoge... 17989248 - Hitchhiking effects of recurrent beneficial amino acid substitutions in the drosophila ... 7066188 - Changes in epidermal acid phosphatase levels in response to chemical irritation. |
Publication Detail:
|
Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
|
Title: Molecular endocrinology (Baltimore, Md.) Volume: 14 ISSN: 0888-8809 ISO Abbreviation: Mol. Endocrinol. Publication Date: 2000 Mar |
Date Detail:
|
Created Date: 2000-04-21 Completed Date: 2000-04-21 Revised Date: 2008-11-21 |
Medline Journal Info:
|
Nlm Unique ID: 8801431 Medline TA: Mol Endocrinol Country: UNITED STATES |
Other Details:
|
Languages: eng Pagination: 401-20 Citation Subset: IM |
Affiliation:
|
Department of Biochemistry, College of Medicine, University of Arizona, Tuscon 85724, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Amino Acid Sequence Amino Acid Substitution Animals Bone Density / genetics COS Cells / drug effects Calcitriol / pharmacology Cercopithecus aethiops DNA / metabolism Fibroblasts / metabolism Genetic Predisposition to Disease Genotype Humans Molecular Sequence Data Mutagenesis, Site-Directed Osteoporosis / genetics Polymorphism, Genetic Protein Isoforms / chemistry, genetics, physiology* Protein Structure, Tertiary Receptors, Calcitriol / chemistry, genetics, physiology* Transcription Factor TFIIB Transcription Factors / metabolism* Transcriptional Activation* Zinc Fingers / physiology |
| Grant Support | |
ID/Acronym/Agency:
|
AR-15781/AR/NIAMS NIH HHS; DK-33351/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Protein Isoforms; 0/Receptors, Calcitriol; 0/Transcription Factor TFIIB; 0/Transcription Factors; 32222-06-3/Calcitriol; 9007-49-2/DNA |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Regulation of tissue factor gene expression in human endometrium by transcription factors Sp1 and Sp...
Next Document: Endocrine disrupting chemicals, phthalic acid and nonylphenol, activate Pregnane X receptor-mediated...