Bone density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Up to 60% of women suffer osteoporotic fractures as a result of low bone density, which is under strong genetic control acting through effects on bone turnover. Here we show that common allelic variants in the gene encoding the vitamin D receptor can be used to predict differences in bone density, accounting for up to 75% of the total genetic effect on bone density in healthy individuals. The genotype associated with lower bone density was overrepresented in postmenopausal women with bone densities more than 2 standard deviations below values in young normal women. The molecular mechanisms by which bone density is regulated by the vitamin D receptor gene are not certain, although allelic differences in the 3' untranslated region may alter messenger RNA levels. These findings could open new avenues to the development and targeting of prophylactic interventions. It follows that other pathophysiological processes considered to be subject to complex multifactorial genetic regulation may also be modulated by a single gene with pleiotropic transcriptional actions.
Two functionally distinct classes of coactivators are recruited by liganded estrogen receptor, the DRIP/Mediator complex and p160 proteins, although the relative dynamics of recruitment is unclear. Previously, we have shown a direct, estradiol-dependent interaction between the DRIP205 subunit of the DRIP complex and the estrogen receptor (ER) AF2 domain. Here we demonstrate the in vivo recruitment of other endogenous DRIP subunits to ER in response to estradiol treatment in MCF-7 cells. To explore the relationship between DRIP and p160 coactivators, we examined the kinetics of coactivator recruitment to the ER target promoter, pS2, by chromatin immunoprecipitation. We observed a cyclic association and dissociation of coactivators with the promoter, with recruitment of p160s and DRIPs occurring in opposite phases, suggesting an exchange between these coactivator complexes at the target promoter.The actions of estradiol are mediated by two isoforms of the estrogen receptor (ER), 1 ER␣ and ER, which function as ligand-regulated transcription factors. The liganded ER homodimer binds the promoters of target genes and interacts with coactivators to facilitate transcriptional activation (1). A number of coactivators interact with the C-terminal activation domain (AF2) in a ligand-dependent manner and have been implicated in ER-mediated transcription. One class of coactivators, collectively termed the p160 family, includes SRC1/ NCoA-1, TIF2/GRIP1/NCoA-2, and pCIP/ACTR/AIB1 (reviewed in Refs. 16 and 23). The p160 coactivators not only possess weak histone acetyltransferase activity but also recruit CBP/p300 (2), presumably leading to the generation of an open chromatin structure at the promoter (3). A second distinct class of coactivators, alternatively called DRIP, ARC, or TRAP (4, 5), comprises a multi-protein complex that interacts with liganded nuclear receptors, including ER␣ and ER, via the DRIP205/ TRAP220 subunit (6 -10). The DRIP complex shares several subunits with the mammalian Mediator complex, suggesting that it functions in the direct recruitment of RNA polymerase II to the promoter (11).It is evident that both p160s and DRIP205 play a key role in ER-mediated transcription (12-15), and despite the functional distinction between the p160 coactivators and the DRIP complex, the molecular determinants of the interactions between these coactivators and ER appear to be very similar. Both classes of coactivators interact with the receptor AF2 via LXXLL signature motifs (16), and the same residues in the ER␣-AF2 are critical for interactions with both p160s and DRIP205 (6), raising the question of whether these complexes are utilized by the receptor dimer simultaneously or sequentially. It has been reported that ACTR can be acetylated by CBP/p300, leading to the dissociation of p160 coactivator complexes from the promoter-bound ER (17), suggesting a mechanism whereby coactivator exchange may take place. Recently, spectroscopic methods have been used to demonstrate that the stoichiometry of the SRC1/ER␣/E 2 compl...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.