Estrogen Receptor (ER)-α, but Not ER-β, Mediates Regulation of the Insulin-like Growth Factor I Gene by Antiestrogens
The importance of insulin-like growth factor I (IGF-I) on maintenance of skeletal integrity has been widely recognized. Although osteoblasts secrete some IGF-I, the liver is the primary endocrine source for IGF-I. We have studied the regulation of the human IGF-I promoter in the hepatocyte cell line...
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Published in | The Journal of biological chemistry Vol. 276; no. 38; p. 35444 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
21.09.2001
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Online Access | Get full text |
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Summary: | The importance of insulin-like growth factor I (IGF-I) on maintenance of skeletal integrity has been widely recognized. Although
osteoblasts secrete some IGF-I, the liver is the primary endocrine source for IGF-I. We have studied the regulation of the
human IGF-I promoter in the hepatocyte cell line Hep3B, and we have shown that the IGF-I promoter, when co-transfected in
Hep3B cells together with an estrogen receptor (ER)-α expression vector, was transcriptionally regulated by raloxifene or
raloxifene-like molecules but not by 17β-estradiol and 4(OH)-tamoxifen. The induction mediated by raloxifene is antagonized
by 17β-estradiol and mediated selectively by ER-α, but not by ER-β. Transfer of IGF-I promoter sequences from â733 to â65
or from â375 to â65 to a minimal Fos promoter resulted in a comparable responsiveness to raloxifene. This region contains
two CAAT/enhancer-binding protein sites and an activator protein 1 site, both of which have been shown to be involved in estrogen
receptor-mediated transactivation. When the CAAT/enhancer-binding protein sites were mutated in a construct bearing the sequence
from â375 to â65 in front of the minimal Fos promoter, raloxifene induction was reduced, whereas mutation of the other elements
did not affect induction. In addition, using chimeric proteins, we delineated the domains of ER-α that confer to ER-α transactivation
abilities on the IGF-I promoter that are not exhibited by ER-β. These data shed new light on the mechanism of action of antiestrogens
and might help explain, at least in part, the bone-protective effects observed for some antiestrogens in ovariectomized animals. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M105418200 |