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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All-trans-retinoic acid receptors (RAR) and 9-cis-retinoic acid receptors (RXR) are nuclear receptors known to cooperatively activate transcription from retinoid-regulated promoters. By comparing the transactivating properties of RAR and RXR in P19 cells using either plasmid or chromosomal reporter genes containing the mRAR beta 2 gene promoter, we found contrasting patterns of transcriptional regulation in each setting. Cooperativity between RXR and RAR occurred at all times with transiently introduced promoters, but was restricted to a very early stage (<3 h) for chromosomal promoters. This time-dependent loss of cooperativity was specific for chromosomal templates containing two copies of a retinoid-responsive element (RARE) and was not influenced by the spacing between the two RAREs. This loss of cooperativity suggested a delayed acquisition of RAR full transcriptional competence because (i) cooperativity was maintained at RAR ligand subsaturating concentrations, (ii) overexpression of SRC-1 led to loss of cooperativity and even to strong repression of chromosomal templates activity, and (iii) loss of cooperativity was observed when additional cis-acting response elements were activated. Surprisingly, histone deacetylase inhibitors counteracted this loss of cooperativity by repressing partially RAR-mediated activation of chromosomal promoters. Loss of cooperativity was not correlated to local histone hyperacetylation or to alteration of constitutive RNA polymerase II (RNAP) loading at the promoter region. Unexpectedly, RNAP binding to transcribed regions was correlated to the RAR activation state as well as to acetylation levels of histones H3 and H4, suggesting that RAR acts at the mRAR beta promoter by triggering the switch from an RNA elongation-incompetent RNAP form towards an RNA elongation-competent RNAP.
Mol Cell Biol 2002 Mar
PMID:Chromosomal integration of retinoic acid response elements prevents cooperative transcriptional activation by retinoic acid receptor and retinoid X receptor. 1183 11

Thyroid hormone receptors (TRs) are ligand-gated transcription factors. Recently, many coregulator proteins have been identified that interact with steroid/TRs and are required for the activation or repression of hormone sensitive genes. We tested whether steroid receptor coactivator-1 (SRC-1) and nuclear corepressor (N-CoR) expression is altered by hypothyroidism in rat brains on gestational day 16 and postnatal day 15. We found that both SRC-1 and N-CoR mRNA levels were decreased in the cortex and dentate gyrus of 6-n-propyl-2 thiouracil treated rats only on P15, while mRNA levels for both genes were increased in the same CA3 region of the brains. These findings do not support the idea that cofactors are involved in the compensatory mechanisms for conserving TH action, but they do suggest that hypothyroidism affects the responsiveness of tissues to steroid hormones by altering the expression of necessary cofactors.
Mol Cell Endocrinol 2002 Jan 15
PMID:Thyroid hormone exerts site-specific effects on SRC-1 and NCoR expression selectively in the neonatal rat brain. 1185 Jan 21

In order to minimize the risks of endometrial cancer and the development of resistance to antiestrogen therapy, we have synthesized the orally active antiestrogen EM-652 which is the most potent of the known antiestrogens and exerts pure antiestrogenic activity in the mammary gland and endometrium. EM-652 inhibits the AF-1 and AF-2 functions of both ERalpha and beta while the inhibitory action of OH-TAM is limited to AF-2. EM-652, thus, inhibits Ras-induced transcriptional activity and blocks SRC-1-stimulated activity of the two receptors. The absence of blockade of AF-1 by OH-TAM could explain why resistance develops to Tamoxifen treatment. Not only the development, but also the growth of established DMBA-induced mammary carcinoma is inhibited by treatment with EM-800, the prodrug of EM-652. EM-652 is the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro. When incubated with human Ishikawa endometrial carcinoma cells, EM-800 has no stimulatory effect on the estrogen-sensitive parameter alkaline phosphatase activity. When administered to ovariectomized animals, EM-800 prevents bone loss, and lowers serum cholesterol and triglyceride levels. EM-800 has shown benefits in women with breast cancer who had failed Tamoxifen. The above-summarized preclinical and clinical data clearly suggest the interest of studying this compounds in the neoadjuvant and adjuvant settings and, most importantly, for the prevention of breast and uterine cancer.
J Steroid Biochem Mol Biol 2001 Dec
PMID:EM-652 (SCH57068), a pure SERM having complete antiestrogenic activity in the mammary gland and endometrium. 1185 Feb 28

The crystal structure of the ligand binding domain (LBD) of the estrogen-related receptor 3 (ERR3) complexed with a steroid receptor coactivator-1 (SRC-1) peptide reveals a transcriptionally active conformation in absence of any ligand. The structure explains why estradiol does not bind ERRs with significant affinity. Docking of the previously reported ERR antagonists, diethylstilbestrol and 4-hydroxytamoxifen, requires structural rearrangements enlarging the ligand binding pocket that can only be accommodated with an antagonist LBD conformation. Mutant receptors in which the ligand binding cavity is filled up by bulkier side chains still interact with SRC-1 in vitro and are transcriptionally active in vivo, but are no longer efficiently inactivated by diethylstilbestrol or 4-hydroxytamoxifen. These results provide structural and functional evidence for ligand-independent transcriptional activation by ERR3.
Mol Cell 2002 Feb
PMID:Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. 1186 4

To clarify the physiological significance of the intranuclear speckled distribution, or foci formation, of liganded steroid receptors, the subnuclear distribution of green (GFP), yellow (YFP), and cyan (CFP) fluorescent protein-tagged receptors and coactivators was investigated. The foci formation of 5 alpha-dihydrotestosterone (DHT)-bound AR-GFP in COS7 cells was abolished by the cotransfection of a CBP Delta (118-2393) fragment eliciting a dominant negative effect on the transactivation capacity of the AR. The N-terminal AR fragment (AR-AF-1-YFP), which has a strong constitutive transactivation function, formed foci without DHT, whereas the C-terminal AR fragment (AR-AF-2-CFP), which has a quite low transactivation function, was distributed homogeneously even in the presence of DHT. The reporter gene assay showed a synergism between the transactivation functions of AR-AF-1 and AR-AF-2. This synergism was not reflected by the above two-dimensional imaging. In contrast, a three-dimensional imaging method clearly showed a difference in the intranuclear spatial distribution. The DHT-bound wild-type AR-GFP alone or AR-AF-1-YFP plus DHT-bound AR-AF-2-CFP was distributed as approximately 300 discrete spots in one nucleus, whereas AR-AF-1-YFP alone was distributed as one volume in a reticular pattern. Furthermore, not only AR but also the glucocorticoid receptor-YFP, ER alpha -GFP, and YFP-tagged SRC-1, TIF2, and CBP were found to be accumulated in identical spots in the presence of ligand. All of the above results indicate that CBP is one of the factors essential for foci formation of the AR, and may propose the hypothesis that transcriptionally activated steroid receptors, regardless of the type of receptor, are transferred to common compartments (foci) and form a complex with coactivators, and this process is essential to full transactivation.
Mol Endocrinol 2002 Apr
PMID:The presence of both the amino- and carboxyl-terminal domains in the AR is essential for the completion of a transcriptionally active form with coactivators and intranuclear compartmentalization common to the steroid hormone receptors: a three-dimensional imaging study. 1192 66

The intracellular localization of transcriptionally active green fluorescent protein (GFP) chimeras linked to PPARs for human PPAR alpha (GFP-PPARh alpha) and mouse PPAR alpha, beta, and gamma 1 (GFP-PPARm alpha, GFP-PPARm beta, and GFP-PPARm gamma, respectively) was examined in the mouse hepatoma cell line, Hepa-1, using fluorescence microscopy. A predominantly nuclear and diffuse distribution of each isoform was found in both the presence and absence of specific ligands for each receptor. GFP-PPARm alpha-G (containing a Glu282Gly substitution of PPARm alpha) and a phosphorylation mutant, GFP-PPARm gamma-A (containing a Ser82Ala substitution of PPARm gamma), exhibited altered transcriptional activities, but displayed similar intracellular localization patterns compared with their respective wild-type receptors. Coexpression of nuclear receptor corepressor suppressed, whereas steroid receptor coactivator-1 enhanced the transcriptional activity of each of the GFP-PPAR isoforms, but did not discernibly alter their intracellular distributions, both in the presence and absence of PPAR ligands. Interestingly, coexpression of the obligate heterodimeric partner of PPARs, RXR alpha, resulted in an intranuclear redistribution of the GFP-PPARm gamma isoform characterized by a reticulated pattern of the green fluorescent label for PPAR gamma within the nucleus, but not in nucleoli, and a heightened concentration of the fluorescent label surrounding nucleolar structures and at the nuclear membrane. Conversely, coexpression of yellow fluorescent protein-RXR alpha and native PPARm gamma resulted in a similar distribution of the yellow fluorescent tag. This localization pattern was not discernibly altered by PPAR gamma or RXR alpha-specific ligands. These results implicate RXR alpha in the nuclear reorganization of PPAR gamma and suggest that PPAR gamma colocalizes with RXR alpha at specific locations within the nucleus independent of added ligand.
Mol Endocrinol 2002 Apr
PMID:Selective intranuclear redistribution of PPAR isoforms by RXR alpha. 1192 67

Steroidogenic factor-1 (SF-1) is a member of the nuclear receptor superfamily that plays essential roles in the development of endocrine organs. Steroid receptor coactivator 1 and transcription intermediary factor 2 (TIF2) belong to the p160 coactivator family that mediates transcriptional activation by several nuclear receptors, including SF-1. Here, it is reported that another of the p160 coactivators, p/CIP, interacts with SF-1 through the activation function-2 domain. Both p300/CBP/cointegrator-associated protein (p/CIP) and TIF2 potentiated SF-1-mediated transcription from two reporter gene constructs in transfected nonsteroidogenic COS-1 cells and in adrenocortical Y1 cells. PKA was shown to stimulate SF-1 transcriptional activity, and coexpression of p/CIP together with the PKA catalytic subunit stimulated SF-1-mediated transactivation even further. In contrast, PKA catalytic subunit overexpression impaired the ability of TIF2 to potentiate SF-1-dependent transcription. Activation of PKA also inhibited the TIF2-mediated coactivation of other nuclear receptors such as PPAR alpha/-gamma and liver X receptor-alpha. The TIF2 mRNA levels were not affected by PKA, but instead we found that PKA activation led to a decrease in the levels of TIF2 protein. Moreover, the C-terminal activation domain 2 of TIF2 was required for the inhibitory effect of PKA, suggesting that this region is the target for the PKA-mediated down-regulation. Thus, in contrast to the regulation of p/CIP and steroid receptor coactivator 1, we suggest that activation of PKA leads to selective down-regulation of TIF2 and subsequently repression of TIF2 coactivator function.
Mol Endocrinol 2002 Apr
PMID:The nuclear receptor coactivators p300/CBP/cointegrator-associated protein (p/CIP) and transcription intermediary factor 2 (TIF2) differentially regulate PKA-stimulated transcriptional activity of steroidogenic factor 1. 1192 73

The estrogen receptor (ER), a member of the nuclear hormone receptor superfamily important in human physiology and disease, recruits coactivators which modify local chromatin structure. Here we describe effects of ER on large-scale chromatin structure as visualized in live cells. We targeted ER to gene-amplified chromosome arms containing large numbers of lac operator sites either directly, through a lac repressor-ER fusion protein (lac rep-ER), or indirectly, by fusing lac repressor with the ER interaction domain of the coactivator steroid receptor coactivator 1. Significant decondensation of large-scale chromatin structure, comparable to that produced by the approximately 150-fold-stronger viral protein 16 (VP16) transcriptional activator, was produced by ER in the absence of estradiol using both approaches. Addition of estradiol induced a partial reversal of this unfolding by green fluorescent protein-lac rep-ER but not by wild-type ER recruited by a lac repressor-SRC570-780 fusion protein. The chromatin decondensation activity did not require transcriptional activation by ER nor did it require ligand-induced coactivator interactions, and unfolding did not correlate with histone hyperacetylation. Ligand-induced coactivator interactions with helix 12 of ER were necessary for the partial refolding of chromatin in response to estradiol using the lac rep-ER tethering system. This work demonstrates that when tethered or recruited to DNA, ER possesses a novel large-scale chromatin unfolding activity.
Mol Cell Biol 2002 May
PMID:Alteration of large-scale chromatin structure by estrogen receptor. 1197 75

In the past few years, many nuclear receptor coactivators have been identified and shown to be an integral part of receptor action. The most frequently studied of these coactivators are members of the steroid receptor coactivator (SRC) family, SRC-1, TIF2/GRIP1/SRC-2, and pCIP/ACTR/AIB-1/RAC-3/TRAM-1/SRC-3. In this report, we describe the biochemical purification of SRC-1 and SRC-3 protein complexes and the subsequent identification of their associated proteins by mass spectrometry. Surprisingly, we found association of SRC-3, but not SRC-1, with the I kappa B kinase (IKK). IKK is known to be responsible for the degradation of I kappa B and the subsequent activation of NF-kappa B. Since NF-kappa B plays a key role in host immunity and inflammatory responses, we therefore investigated the significance of the SRC-3-IKK complex. We demonstrated that SRC-3 was able to enhance NF-kappa B-mediated gene expression in concert with IKK. In addition, we showed that SRC-3 was phosphorylated by the IKK complex in vitro. Furthermore, elevated SRC-3 phosphorylation in vivo and translocation of SRC-3 from cytoplasm to nucleus in response to tumor necrosis factor alpha occurred in cells, suggesting control of subcellular localization of SRC-3 by phosphorylation. Finally, the hypothesis that SRC-3 is involved in NF-kappa B-mediated gene expression is further supported by the reduced expression of interferon regulatory factor 1, a well-known NF-kappa B target gene, in the spleens of SRC-3 null mutant mice. Taken together, our results not only reveal the IKK-mediated phosphorylation of SRC-3 to be a regulated event that plays an important role but also substantiate the role of SRC-3 in multiple signaling pathways.
Mol Cell Biol 2002 May
PMID:Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase. 1197 85

Recent research has highlighted the functional importance of chromatin structure in transcriptional regulation. We have used Xenopus oocytes as a model system to investigate the action of AR in the context of chromatin. By manipulating the levels of AR expression, we have observed both agonist-dependent and -independent activation by AR. Expression of AR at relatively low levels resulted in strong agonist-dependent activation, whereas high levels of AR also led to hormone-independent activation. By using gel mobility shift and deoxyribonuclease I footprinting assays, we demonstrate that AR expressed in Xenopus oocytes binds to a consensus androgen response element in vitro in a ligand-independent manner. Expression of the coactivators steroid receptor coactivator-1, receptor-associated coactivator-3, and p300 stimulated both agonist-dependent and -independent activation by AR. Furthermore, this hormone-independent activity of AR is also observed in mammalian cells. Antagonists such as casodex can inhibit hormone-independent activity of AR, and this inhibition appears to correlate with the enhanced association with corepressor silencing mediator of retinoid and thyroid hormone receptors. Altogether, our studies reveal that AR has a capacity to activate transcription in a ligand-independent manner.
Mol Endocrinol 2002 May
PMID:AR possesses an intrinsic hormone-independent transcriptional activity. 1198 Oct 28


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