Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
6
|
| pubmed:dateCreated |
1994-3-22
|
| pubmed:abstractText |
Hemophilia B-Leyden is characterized by the gradual amelioration of bleeding after the onset of puberty. All Leyden phenotype mutations found to date lie within the Leyden-specific region, which spans roughly nt-40 to +20 in the 5' end of the human factor IX gene. With HepG2 cell nuclear extracts, the Leyden-specific region and its immediate neighboring region of the normal factor IX gene showed five DNase I footprints: FP-I (nt +4 to +19), FP-II (nt -16 to -3), FP-III (nt -27 to -19), FP-IV (nt -67 to -49), and FP-V (nt -99 to -77). Protein binding affinities of short oligonucleotides containing sequences of FP-I, FP-II, or FP-III were substantially reduced in the presence of Leyden phenotype mutations in these areas, correlating well with the negative effects of these mutations on factor IX gene expression. A Leyden phenotype mutation at nt -20 (T to A) caused a loss of both footprints FP-III and FP-II but generated a new footprint, FP-III' (nt -34 to -23), partially overlapping with FP-III, indicating mutation-dependent competitive protein binding at these sites. Although the FP-III' area contains an androgen responsive element-like sequence, the nuclear protein that binds at FP-III' is not androgen receptor. The protein was not recognized by anti-androgen receptor antibody and, furthermore, was present not only in liver but also in both androgen receptor-positive and androgen receptor-negative cells in electrophoretic mobility shift assays. The nuclear concentration of this protein increased significantly upon treatment of the HepG2 cells with testosterone. Its binding affinity to an oligonucleotide (-32sub) containing the FP-III' sequence was greatly reduced in the presence of exogenous androgen receptor, suggesting a possible interaction of this protein with androgen receptor. The affinities of both this protein and a protein which binds to FP-III (presumably HNF-4) to -32sub with a mutation at nt -26 were grossly lowered. These findings suggest that the amelioration of hemophilia B-Leyden with a mutation at nt -20 after puberty involves binding of a specific non-androgen receptor nuclear protein at FP-III' and it is able to substitute for the function of a protein bound at FP-III in the normal gene optimally through its elevated interaction with androgen receptor upon a surge of testosterone.(ABSTRACT TRUNCATED AT 400 WORDS)
|
| pubmed:grant | |
| pubmed:commentsCorrections | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Deoxyribonuclease I,
http://linkedlifedata.com/resource/pubmed/chemical/Factor IX,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Androgen,
http://linkedlifedata.com/resource/pubmed/chemical/Testosterone,
http://linkedlifedata.com/resource/pubmed/chemical/factor IX Leyden
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Feb
|
| pubmed:issn |
0006-2960
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
15
|
| pubmed:volume |
33
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1580-91
|
| pubmed:dateRevised |
2007-11-14
|
| pubmed:meshHeading |
pubmed-meshheading:8312279-Animals,
pubmed-meshheading:8312279-Base Sequence,
pubmed-meshheading:8312279-Binding Sites,
pubmed-meshheading:8312279-Cell Line,
pubmed-meshheading:8312279-Cercopithecus aethiops,
pubmed-meshheading:8312279-Cricetinae,
pubmed-meshheading:8312279-DNA,
pubmed-meshheading:8312279-DNA-Binding Proteins,
pubmed-meshheading:8312279-Deoxyribonuclease I,
pubmed-meshheading:8312279-Factor IX,
pubmed-meshheading:8312279-Humans,
pubmed-meshheading:8312279-Male,
pubmed-meshheading:8312279-Molecular Sequence Data,
pubmed-meshheading:8312279-Mutation,
pubmed-meshheading:8312279-Rats,
pubmed-meshheading:8312279-Rats, Sprague-Dawley,
pubmed-meshheading:8312279-Receptors, Androgen,
pubmed-meshheading:8312279-Regulatory Sequences, Nucleic Acid,
pubmed-meshheading:8312279-Testosterone,
pubmed-meshheading:8312279-Transcription, Genetic,
pubmed-meshheading:8312279-Tumor Cells, Cultured
|
| pubmed:year |
1994
|
| pubmed:articleTitle |
Regulatory mechanism of human factor IX gene: protein binding at the Leyden-specific region.
|
| pubmed:affiliation |
Department of Human Genetics, University of Michigan Medical Center, Ann Arbor 48109-0618.
|
| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
|