Linked Life Data

10893309

Source:http://linkedlifedata.com/resource/pubmed/id/10893309

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2000-8-3
pubmed:abstractText
The hormone 1alpha,25(OH)(2)-vitamin D(3) (125D) binds to its nuclear receptor (VDR) to stimulate gene transcription activity. Inversion of configuration at C-20 of the side chain to generate 20-epi-1alpha,25(OH)(2)D(3) (20E-125D) increases transcription 200-5000-fold over 125D with its 20-normal (20N) side chain. This enhancement has been attributed to the VDR ligand-binding domain (LBD) having different contact sites for 20N and 20E side chains that generate different VDR conformations. We synthesized 1alpha, 25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D(3) (Gemini) with two six-carbon side chains (both 20N and 20E orientations). Energy minimization calculations indicate the Gemini side chain possesses significantly more energy minima than either 125D or 20E-125D (2346, 207, and 127 minima, respectively). We compared activities of 125D, 20E-125D, and Gemini, respectively, in several assays: binding to wild-type (100%, 147%, and 38%) and C-terminal-truncated mutant VDR; transcriptional activity (of the transfected osteopontin promoter in ROS 17/2.8 cells: ED(50) 10, 0.005, and 1.0 nM); mediation of conformational changes in VDR assessed by protease clipping (major trypsin-resistant fragment of 34, 34, and 28 kDa). For inhibition of cellular clonal growth of human leukemia (HL-60) and breast cancer (MCF7) cell lines, the ED(50)(125D)/ED(50)(Gem) was respectively 380 and 316. We conclude that while Gemini readily binds to the VDR and generates unique conformational changes, none of them is able to permit a superior gene transcription activity despite the presence of a 20E side chain.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
13
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2719-30
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:10893309-Animals, pubmed-meshheading:10893309-Binding, Competitive, pubmed-meshheading:10893309-Calcitriol, pubmed-meshheading:10893309-Cell Division, pubmed-meshheading:10893309-Cell Line, pubmed-meshheading:10893309-Chickens, pubmed-meshheading:10893309-Clone Cells, pubmed-meshheading:10893309-Humans, pubmed-meshheading:10893309-Ligands, pubmed-meshheading:10893309-Models, Molecular, pubmed-meshheading:10893309-Osteopontin, pubmed-meshheading:10893309-Promoter Regions, Genetic, pubmed-meshheading:10893309-Protein Conformation, pubmed-meshheading:10893309-Receptors, Calcitriol, pubmed-meshheading:10893309-Receptors, Somatotropin, pubmed-meshheading:10893309-Recombinant Fusion Proteins, pubmed-meshheading:10893309-Response Elements, pubmed-meshheading:10893309-Sialoglycoproteins, pubmed-meshheading:10893309-Thymidine Kinase, pubmed-meshheading:10893309-Transcription, Genetic, pubmed-meshheading:10893309-Transfection, pubmed-meshheading:10893309-Tumor Cells, Cultured
pubmed:year
2000
pubmed:articleTitle
Characterization of a novel analogue of 1alpha,25(OH)(2)-vitamin D(3) with two side chains: interaction with its nuclear receptor and cellular actions.
pubmed:affiliation
Departments of Biochemistry and Chemistry and Division of Biomedical Sciences, University of California, Riverside, California 92521, USA. Norman@ucrac1,ucr.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't