Estrogens: from classical endocrine action to tissue selective action.
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Animals↗
Biomedical subjects
B J Cheskis
Publications and source records attributed to B J Cheskis.
Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands.
Analysis of estrogen receptor alpha and beta interplay with other transcription factors is critical to the understanding of how small molecules, the cognate ligands for these receptors, selectively regulate the mode and amplitude of gene transcription by affecting receptor activity. To better understand the molecular mechanisms of selective action of estrogen receptor ligands, we characterized estrogen receptor alpha and beta (ER) interaction with the p160 family of coactivators. We also investigated how these interactions are affected by binding of specific ligands. We show that ER alpha and beta utilize different LXXLL motifs for their interaction with p160 family members. We found that significant differences exist between the affinity of the nuclear receptor interacting domain (NRID) and interaction of separate LXXLL motifs with ERs. This result indicates that a single LXXLL motif is unlikely to be sufficient for interaction with receptors, and that regions other than LXXLL motifs also participate in ER-p160 complex formation. We found that ER alpha and beta have strong affinity preferences for particular coactivators. These results suggest that ER-mediated transcription is not driven by a random mixture of ER-coactivator complexes. We also show that some ER ligands are functionally specific. We describe a ligand that binds to both receptors, but enhances only ER beta interaction with SRC1 and SRC3 while exhibiting little effect on the ER alpha interaction with these proteins. Finally, we provide data that suggest how genistein may selectively recruit coactivators when liganded to ERs. It enhances the interaction of ERs with SRC1 and SRC3, but demonstrates a minimal effect on receptor interaction with DRIP205 and CBP.
Acetyltransferases↗
Functional interactions between the estrogen receptor and DRIP205, a subunit of the heteromeric DRIP coactivator complex.
Nuclear receptors regulate transcription in direct response to their cognate hormonal ligands. Ligand binding leads to the dissociation of corepressors and the recruitment of coactivators. Many of these factors, acting in large complexes, have emerged as potential chromatin remodelers through intrinsic histone modifying activities. In addition, other ligand-recruited complexes appear to act more directly on the transcriptional apparatus. The DRIP complex is a 15-subunit complex required for nuclear receptor transcriptional activation in vitro. It is recruited to the receptor in response to ligand through specific interactions of one subunit, DRIP205. We present evidence that DRIP205 interacts with another member of the steroid receptor subfamily, estrogen receptor (ER). This interaction occurs in an agonist-stimulated fashion which in turn is inhibited by several ER antagonists. In vivo, a fragment of DRIP205 containing only its receptor interacting region acts to selectively inhibit ER's ability to activate transcription in response to estradiol. These observations suggest a key role for the DRIP coactivator complex in estrogen-ER signaling.
Animals↗
A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity.
Estrogen receptors ERalpha and ERbeta are members of the family of nuclear hormone receptors and act as ligand-inducible transcriptional factors, which regulate the expression of target genes on binding to cognate response elements. We report here the characterization of steroid receptor coactivator-3 (SRC-3), a coactivator of nuclear receptor transcription that is a member of a family of steroid receptor coactivators that includes SRC-1 and transcription intermediate factor-2. SRC-3 enhanced ERalpha and progesterone receptor-stimulated gene transcription in a ligand-dependent manner, but stimulation of ERbeta-mediated transcription was not observed. Protein-protein interaction assays, including real-time interaction analyses with BIAcore, demonstrated that the affinity of the ERalpha interaction with SRC-3 was much higher than that observed for the ERbeta interaction with SRC-3. Mutational analysis suggests a potential interplay between the transactivation function-1 and -2 domains of ERalpha and SRC-3. Furthermore, an intrinsic transactivation function was observed in the C-terminal half of SRC-3. Finally, SRC-3 was differentially expressed in various tissues and, among several tumor cells examined, was most abundant in the nuclear fraction of MCF-7 breast cancer cells. Therefore, SRC-3, a third member of a family of steroid receptor coactivators, has a distinct tissue distribution and intriguing selectivity between ERalpha and ERbeta.
Acetyltransferases↗
Estrogen receptor ligands modulate its interaction with DNA.
The estrogen receptor (ER) belongs to a superfamily of ligand-inducible transcription factors. Functions of these proteins (dimerization, DNA binding, and interaction with other transcription factors) are modulated by binding of their corresponding ligands. It is, however, controversial whether various ER ligands affect the receptor's ability to bind its specific DNA element (ERE). By using real time interaction analysis we have investigated the kinetics of human (h)ER binding to DNA in the absence and presence of 17beta-estradiol, 17alpha-ethynyl estradiol, analogs of tamoxifen, raloxifene, and ICI-182,780. We show that ligand binding dramatically influences the kinetics of hER interaction with specific DNA. We have found that binding of estradiol induces the rapid formation of a relatively unstable ER.ERE complex, and binding of ICI-182,780 leads to slow formation (ka is approximately 10 times lower) of a stable receptor-DNA complex (kd is almost 2 orders of magnitude lower). Therefore, binding of estradiol accelerates the frequency of receptor-DNA complex formation more than 50-fold, compared with unliganded ER, and more than 1000-fold compared with ER liganded with ICI-182,780. We hypothesize that a correlation exists between the rate of gene transcription and the frequency of receptor-DNA complex formation. We further show that a good correlation exists between the kinetics of hER-ERE interaction induced by a ligand and its biological effect.
DNA-Binding Proteins↗