Source:http://linkedlifedata.com/resource/pubmed/id/21873215
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
36
|
| pubmed:dateCreated |
2011-9-7
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| pubmed:abstractText |
The estrogen receptor (ER) is a ligand-dependent transcription factor containing two transcriptional activation domains. AF-1 is in the N terminus of the receptor protein and AF-2 activity is dependent on helix 12 of the C-terminal ligand-binding domain. Two point mutations of leucines 543 and 544 to alanines (L543A, L544A) in helix 12 minimized estrogen-dependent transcriptional activation and reversed the activity of the estrogen antagonists ICI182780 (ICI) and tamoxifen (TAM) into agonists in a similar manner that TAM activated WT ER? through AF-1 activation. To evaluate the physiological role of AF-1 and AF-2 for the tissue-selective function of TAM, we generated an AF-2-mutated ER? knock-in (AF2ERKI) mouse model. AF2ERKI homozygote female mice have hypoplastic uterine tissue and rudimentary mammary glands similar to ER?-KO mice. Female mice were infertile as a result of anovulation from hemorrhagic cystic ovaries and elevated serum LH and E2 levels, although the mutant ER? protein is expressed in the AF2ERKI model. The AF2ERKI phenotype suggests that AF-1 is not activated independently, even with high serum E2 levels. ICI and TAM induced uterotropic and ER-mediated gene responses in ovariectomized AF2ERKI female mice in the same manner as in TAM- and E2-treated WT mice. In contrast, ICI and TAM did not act as agonists to regulate negative feedback of serum LH or stimulate pituitary prolactin gene expression in a different manner than TAM- or E2-treated WT mice. The functionality of the mutant ER? in the pituitary appears to be different from that in the uterus, indicating that ER? uses AF-1 differently in the uterus and the pituitary for TAM action.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
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| pubmed:month |
Sep
|
| pubmed:issn |
1091-6490
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| pubmed:author | |
| pubmed:issnType |
Electronic
|
| pubmed:day |
6
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| pubmed:volume |
108
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| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
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| pubmed:pagination |
14986-91
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| pubmed:meshHeading |
pubmed-meshheading:21873215-Amino Acid Substitution,
pubmed-meshheading:21873215-Animals,
pubmed-meshheading:21873215-Estrogen Antagonists,
pubmed-meshheading:21873215-Estrogen Receptor alpha,
pubmed-meshheading:21873215-Female,
pubmed-meshheading:21873215-Gene Knock-In Techniques,
pubmed-meshheading:21873215-HeLa Cells,
pubmed-meshheading:21873215-Humans,
pubmed-meshheading:21873215-Luteinizing Hormone,
pubmed-meshheading:21873215-Male,
pubmed-meshheading:21873215-Mammary Glands, Animal,
pubmed-meshheading:21873215-Mice,
pubmed-meshheading:21873215-Mice, Knockout,
pubmed-meshheading:21873215-Organ Specificity,
pubmed-meshheading:21873215-Ovary,
pubmed-meshheading:21873215-Pituitary Gland,
pubmed-meshheading:21873215-Point Mutation,
pubmed-meshheading:21873215-Protein Structure, Tertiary,
pubmed-meshheading:21873215-Tamoxifen,
pubmed-meshheading:21873215-Uterus
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| pubmed:year |
2011
|
| pubmed:articleTitle |
Estrogen receptor ? AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators.
|
| pubmed:affiliation |
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Intramural
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