Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
29
|
| pubmed:dateCreated |
1997-8-18
|
| pubmed:abstractText |
Insulin-like growth factor-I (IGF-I) is a key factor in bone remodeling. In osteoblasts, IGF-I synthesis is enhanced by parathyroid hormone and prostaglandin E2 (PGE2) through cAMP-activated protein kinase. In rats, estrogen loss after ovariectomy leads to a rise in serum IGF-I and an increase in bone remodeling, both of which are reversed by estrogen treatment. To examine estrogen-dependent regulation of IGF-I expression at the molecular level, primary fetal rat osteoblasts were co-transfected with the estrogen receptor (hER, to ensure active ER expression), and luciferase reporter plasmids controlled by promoter 1 of the rat IGF-I gene (IGF-I P1), used exclusively in these cells. As reported, 1 microM PGE2 increased IGF-I P1 activity by 5-fold. 17beta-Estradiol alone had no effect, but dose-dependently suppressed the stimulatory effect of PGE2 by up to 90% (ED50 approximately 0.1 nM). This occurred within 3 h, persisted for at least 16 h, required ER, and appeared specific, since 17alpha-estradiol was 100-300-fold less effective. By contrast, 17beta-estradiol stimulated estrogen response element (ERE)-dependent reporter expression by up to 10-fold. 17beta-Estradiol also suppressed an IGF-I P1 construct retaining only minimal promoter sequence required for cAMP-dependent gene activation, but did not affect the 60-fold increase in cAMP induced by PGE2. There is no consensus ERE in rat IGF-I P1, suggesting novel downstream interactions in the cAMP pathway that normally enhances IGF-I expression in skeletal cells. To explore this, nuclear extract from osteoblasts expressing hER were examined by electrophoretic mobility shift assay using the atypical cAMP response element in IGF-I P1. Estrogen alone did not cause DNA-protein binding, while PGE2 induced a characteristic gel shift complex. Co-treatment with both hormones caused a gel shift greatly diminished in intensity, consistent with their combined effects on IGF-I promoter activity. Nonetheless, hER did not bind IGF-I cAMP response element or any adjacent sequences. These results provide new molecular evidence that estrogen may temper the biological effects of hormones acting through cAMP to regulate skeletal IGF-I expression and activity.
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| pubmed:grant | |
| pubmed:keyword | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Dinoprostone,
http://linkedlifedata.com/resource/pubmed/chemical/Estradiol,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin-Like Growth Factor I,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Estrogen,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jul
|
| pubmed:issn |
0021-9258
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
18
|
| pubmed:volume |
272
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
18132-9
|
| pubmed:dateRevised |
2008-11-21
|
| pubmed:meshHeading |
pubmed-meshheading:9218447-Animals,
pubmed-meshheading:9218447-Binding Sites,
pubmed-meshheading:9218447-Cell Differentiation,
pubmed-meshheading:9218447-Cell Nucleus,
pubmed-meshheading:9218447-Cells, Cultured,
pubmed-meshheading:9218447-Consensus Sequence,
pubmed-meshheading:9218447-Cyclic AMP,
pubmed-meshheading:9218447-DNA-Binding Proteins,
pubmed-meshheading:9218447-Dinoprostone,
pubmed-meshheading:9218447-Estradiol,
pubmed-meshheading:9218447-Fetus,
pubmed-meshheading:9218447-Gene Expression Regulation,
pubmed-meshheading:9218447-Genes, Reporter,
pubmed-meshheading:9218447-Humans,
pubmed-meshheading:9218447-Insulin-Like Growth Factor I,
pubmed-meshheading:9218447-Kinetics,
pubmed-meshheading:9218447-Luciferases,
pubmed-meshheading:9218447-Osteoblasts,
pubmed-meshheading:9218447-Promoter Regions, Genetic,
pubmed-meshheading:9218447-Rats,
pubmed-meshheading:9218447-Rats, Sprague-Dawley,
pubmed-meshheading:9218447-Receptors, Estrogen,
pubmed-meshheading:9218447-Recombinant Fusion Proteins,
pubmed-meshheading:9218447-Transcriptional Activation,
pubmed-meshheading:9218447-Transfection
|
| pubmed:year |
1997
|
| pubmed:articleTitle |
17beta-estradiol potently suppresses cAMP-induced insulin-like growth factor-I gene activation in primary rat osteoblast cultures.
|
| pubmed:affiliation |
Yale University School of Medicine, Section of Plastic Surgery, New Haven, Connecticut 06520-8041, USA. McCarthyTL@maspo3.mas.yale.edu
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.
|