PMID- 10707958
OWN - NLM
STAT- MEDLINE
DCOM- 20000421
LR  - 20220317
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 14
IP  - 3
DP  - 2000 Mar
TI  - The polymorphic N terminus in human vitamin D receptor isoforms influences 
      transcriptional activity by modulating interaction with transcription factor IIB.
PG  - 401-20
AB  - 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.
FAU - Jurutka, P W
AU  - Jurutka PW
AD  - Department of Biochemistry, College of Medicine, University of Arizona, Tuscon 
      85724, USA.
FAU - Remus, L S
AU  - Remus LS
FAU - Whitfield, G K
AU  - Whitfield GK
FAU - Thompson, P D
AU  - Thompson PD
FAU - Hsieh, J C
AU  - Hsieh JC
FAU - Zitzer, H
AU  - Zitzer H
FAU - Tavakkoli, P
AU  - Tavakkoli P
FAU - Galligan, M A
AU  - Galligan MA
FAU - Dang, H T
AU  - Dang HT
FAU - Haussler, C A
AU  - Haussler CA
FAU - Haussler, M R
AU  - Haussler MR
LA  - eng
GR  - AR-15781/AR/NIAMS NIH HHS/United States
GR  - DK-33351/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Protein Isoforms)
RN  - 0 (Receptors, Calcitriol)
RN  - 0 (Transcription Factor TFIIB)
RN  - 0 (Transcription Factors)
RN  - 9007-49-2 (DNA)
RN  - FXC9231JVH (Calcitriol)
SB  - IM
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Bone Density/genetics
MH  - COS Cells/drug effects
MH  - Calcitriol/pharmacology
MH  - Chlorocebus aethiops
MH  - DNA/metabolism
MH  - Fibroblasts/metabolism
MH  - Genetic Predisposition to Disease
MH  - Genotype
MH  - Humans
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Osteoporosis/genetics
MH  - Polymorphism, Genetic
MH  - Protein Isoforms/chemistry/genetics/*physiology
MH  - Protein Structure, Tertiary
MH  - Receptors, Calcitriol/chemistry/genetics/*physiology
MH  - Transcription Factor TFIIB
MH  - Transcription Factors/*metabolism
MH  - *Transcriptional Activation
MH  - Zinc Fingers/physiology
EDAT- 2000/03/09 09:00
MHDA- 2000/04/29 09:00
CRDT- 2000/03/09 09:00
PHST- 2000/03/09 09:00 [pubmed]
PHST- 2000/04/29 09:00 [medline]
PHST- 2000/03/09 09:00 [entrez]
AID - 10.1210/mend.14.3.0435 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2000 Mar;14(3):401-20. doi: 10.1210/mend.14.3.0435.