
<ArticleTitle><prot>Estrogen receptor (ER)-alpha</prot>, but not <prot>ER-beta</prot>, mediates regulation of the <prot>insulin-like growth factor I</prot> gene by antiestrogens.</ArticleTitle>
<AbstractText>The importance of <prot>insulin-like growth factor I</prot> (<prot>IGF-I</prot>) on maintenance of skeletal integrity has been widely recognized. Although osteoblasts secrete some <prot>IGF-I</prot>, the liver is the primary endocrine source for <prot>IGF-I</prot>. We have studied the regulation of the human <prot>IGF-I</prot> promoter in the hepatocyte cell line Hep3B, and we have shown that the <prot>IGF-I</prot> promoter, when co-transfected in Hep3B cells together with an <prot>estrogen receptor (ER)-alpha</prot> expression vector, was transcriptionally regulated by raloxifene or raloxifene-like molecules but not by 17beta-estradiol and 4(OH)-tamoxifen. The induction mediated by raloxifene is antagonized by 17beta-estradiol and mediated selectively by <prot>ER-alpha</prot>, but not by <prot>ER-beta</prot>. Transfer of <prot>IGF-I</prot> promoter sequences from -733 to -65 or from -375 to -65 to a minimal <prot>Fos</prot> promoter resulted in a comparable responsiveness to raloxifene. This region contains two <prot>CAAT/enhancer-binding protein</prot> sites and an <prot>activator protein 1</prot> site, both of which have been shown to be involved in estrogen receptor-mediated transactivation. When the <prot>CAAT/enhancer-binding protein</prot> sites were mutated in a construct bearing the sequence from -375 to -65 in front of the minimal <prot>Fos</prot> 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 <prot>ER-alpha</prot> that confer to <prot>ER-alpha</prot> transactivation abilities on the <prot>IGF-I</prot> promoter that are not exhibited by <prot>ER-beta</prot>. 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.</AbstractText>
