Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have performed a mutagenesis analysis of the 58-amino-acid tau1-core peptide, which represents the core transactivation activity of the tau1 transactivation domain from the glucocorticoid receptor. Mutants with altered activity were identified by phenotypic screening in the yeast Saccharomyces cerevisiae. Most mutants with reduced activity had substitutions of hydrophobic amino acids. Most single-substitution mutants with reduced activity were localized near the N terminus of the tau1-core within a segment that has been shown previously to have a propensity for alpha-helix conformation, suggesting that this helical region is of predominant importance. The particular importance of hydrophobic residues within this region was confirmed by comparing the activities of alanine substitutions of the hydrophobic residues in this and two other helical regions. The hydrophobic residues were shown to be important for the transactivation activity of both the isolated tau1-core and the intact glucocorticoid receptor in mammalian cells. Rare mutations in helical regions I and II gave rise to increased transcriptional activation activity. These mutations increase the hydrophobicity of hydrophobic patches on each of these helices, suggesting a relationship between the hydrophobicity of the patches and transactivation activity. However, certain nonhydrophobic residues are also important for activity. Interestingly, helical region I partially matches a consensus motif found in the retinoic acid receptor, VP16, and several other activator proteins.
Mol Cell Biol 1997 Feb
PMID:Role of hydrophobic amino acid clusters in the transactivation activity of the human glucocorticoid receptor. 900 Dec 47

Retinoids modulate gene activity, cell growth and differentiation by binding to a series of nuclear receptors, i.e., retinoic acid receptors (RARs) or retinoid X receptors. Retinoic acid (RA) inhibition of estrogen receptor (ER)-positive breast carcinoma seems to be mediated through RAR alpha. Estrogens upregulate RAR alpha in ER-positive breast carcinoma cell lines. In this study we examined RAR alpha expression in the ER-positive MCF7 and ER-negative MDA-MB-231 human breast carcinoma cell lines as well as in 10 ER-negative and 9 ER-positive infiltrating ductal breast carcinoma specimens using immunohistochemistry and quantitation by image cytometry. MCF7 cells expressed twofold higher levels of RAR alpha protein than MDA-MB-231 cells. RAR alpha expression, as detected by immunostaining and quantitated by image cytometry, was upregulated in these cells by estradiol. ER-positive breast carcinoma specimens also exhibited approximately two-fold higher RAR alpha levels than their ER-negative counterparts. Thus, RAR alpha expression is significantly elevated in ER-positive breast tumors as assessed by detection and quantitation using immunohistochemical staining and image cytometry, respectively. Whether the decrease in RAR alpha protein levels and loss of RA-mediated growth inhibition in ER-negative tumor plays a role in the increased metastatic potential of ER-negative tumors remains to be determined.
Diagn Mol Pathol 1997 Feb
PMID:Elevated expression of retinoic acid receptor-alpha (RAR alpha) in estrogen-receptor-positive breast carcinomas as detected by immunohistochemistry. 902 36

The transcriptional repressor negative protein 1 (NeP1) binds specifically to the F1 element of the chicken lysozyme gene silencer and mediates synergistic repression by v-ERBA, thyroid hormone receptor, or retinoic acid receptor. Another protein, CCCTC-binding factor (CTCF), specifically binds to 50-bp-long sequences that contain repetitive CCCTC elements in the vicinity of vertebrate c-myc genes. Previously cloned chicken, mouse, and human CTCF cDNAs encode a highly conserved 11-Zn-finger protein. Here, NeP1 was purified and DNA bases critical for NeP1-F1 interaction were determined. NeP1 is found to bind a 50-bp stretch of nucleotides without any obvious sequence similarity to known CTCF binding sequences. Despite this remarkable difference, these two proteins are identical. They have the same molecular weight, and NeP1 contains peptide sequences which are identical to sequences in CTCF. Moreover, NeP1 and CTCF specifically recognize each other's binding DNA sequence and induce identical conformational alterations in the F1 DNA. Therefore, we propose to replace the name NeP1 with CTCF. To analyze the puzzling sequence divergence in CTCF binding sites, we studied the DNA binding of 12 CTCF deletions with serially truncated Zn fingers. While fingers 4 to 11 are indispensable for CTCF binding to the human c-myc P2 promoter site A, a completely different combination of fingers, namely, 1 to 8 or 5 to 11, was sufficient to bind the lysozyme silencer site F1. Thus, CTCF is a true multivalent factor with multiple repressive functions and multiple sequence specificities.
Mol Cell Biol 1997 Mar
PMID:Negative protein 1, which is required for function of the chicken lysozyme gene silencer in conjunction with hormone receptors, is identical to the multivalent zinc finger repressor CTCF. 903 55

Nuclear receptors for retinoic acid are important modulators of epidermal cell proliferation and terminal differentiation. Aberrant expression of retinoic acid receptors (RARs) and retinoid X receptors in the epidermis has been associated with altered differentiation capacity and tumor progression. In this study, we describe a human squamous cell carcinoma line, SCC 12F, which displays reduced RARgamma expression and diminished responsiveness to retinoic acid. When compared with normal keratinocytes or other squamous cell carcinoma lines that display normal levels of RARgamma, several measures of cellular response to retinoic acid are altered in SCC 12F cells, including inhibition of cornified envelope formation, reduction of involucrin mRNA expression, and transcriptional regulation of the involucrin gene. Normal patterns of ligand-dependent transcriptional response were restored upon co-transfection of an expression vector containing either RARalpha or RARgamma. Our findings demonstrate that reduced expression of RAR may have direct functional consequences with regard to keratinocyte differentiation and that the defect may be alleviated by reintroduction of functional receptor.
Mol Pharmacol 1997 Mar
PMID:Functional consequences of reduced retinoic acid receptor gamma expression in a human squamous cell carcinoma line. 905 91

We have found that protoporphyrin IX, which had been regarded as inactive, induces erythroid differentiation. The differentiation-inducing activities of various hemin-related compounds, including hematoporphyrin IX, mesoporphyrin IX, deuteroporphyrin IX and protoporphyrin IX dimethyl ester, suggested certain structural requirements for the activity: 1) the iron moiety of hemin is not essential, and 2) the propionic acid side chains of hemin play an important role. In addition, we have examined the influence of some bioactive factors on hemin/protoporphyrin IX-induced differentiation of K562 cell line. Retinoids and tubulin-disruptors dose-dependently enhanced hemin/protoporphyrin IX-induced differentiation of K562 cells, though they did not themselves induce differentiation. Retinoid antagonists suppressed hemin-induced differentiation. The effects of hemin and/or retinoids on the mRNA expressions of oncogenes (c-myc and c-myb) and retinoic acid receptor genes (rar alpha and rar beta) of K562 cells were analyzed. We also examined the possible involvement of peripheral-type benzodiazepine receptor (PBR) in hemin/protoporphyrin IX-induced differentiation of K562 cells by the use of its ligands. Diazepam itself was revealed to possess differentiation-inducing activity on K562 cells. The PBR-specific ligands modified hemin-induced differentiation. These results suggest a requirement for retinoids (or retinoid-like cofactors) for hemin/protoporphyrin IX-induced differentiation of K562 cells and the involvement of PBR in erythroid differentiation of K562 cell line.
Cell Mol Biol (Noisy-le-grand) 1997 Feb
PMID:Hemin-induced erythroid differentiation of human myeloleukemia K562 cell line and its modification by bioresponse modifiers. 907 96

As the obligate member of most nuclear receptor heterodimers, retinoid X receptors (RXRs) can potentially perform two functions: cooperative binding to hormone response elements and coordinate regulation of target genes by RXR ligands. In this paper we describe allosteric interactions between RXR and two heterodimeric partners, retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs); RARs and PPARs prevent and permit activation by RXR-specific ligands, respectively. By competing for dimerization with RXR on response elements consisting of direct-repeat half-sites spaced by 1 bp (DR1 elements), the relative abundance of RAR and PPAR determines whether the RXR signaling pathway will be functional. In contrast to RAR, which prevents the binding of RXR ligands and recruits the nuclear receptor corepressor N-CoR, PPAR permits the binding of SRC-1 in response to both RXR and PPAR ligands. Overexpression of SRC-1 markedly potentiates ligand-dependent transcription by PPARgamma, suggesting that SRC-1 serves as a coactivator in vivo. Remarkably, the ability of RAR to both block the binding of ligands to RXR and interact with corepressors requires the CoR box, a structural motif residing in the N-terminal region of the RAR ligand binding domain. Mutations in the CoR box convert RAR from a nonpermissive to a permissive partner of RXR signaling on DR1 elements. We suggest that the differential recruitment of coactivators and corepressors by RAR-RXR and PPAR-RXR heterodimers provides the basis for a transcriptional switch that may be important in controlling complex programs of gene expression, such as adipocyte differentiation.
Mol Cell Biol 1997 Apr
PMID:Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors. 912 66

Thyroid hormone and retinoic acid receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors that stimulate the transcription of target genes in the presence of activating ligands and repress transcription in their absence. Transcriptional repression by the thyroid hormone and retinoic acid receptors has been proposed to be mediated by the nuclear receptor corepressor, N-CoR, or the related factor, SMRT (silencing mediator of retinoic acid and thyroid hormone receptors). Recent studies have suggested that transcriptional repression by N-CoR involves a corepressor complex that also contains mSin3A/B and the histone deacetylase, RPD3. In this manuscript, we demonstrate that transcriptional repression by the retinoic acid receptor can be either positively or negatively regulated by changes in the levels of N-CoR expression, suggesting a relatively strict stoichiometric relationship between N-CoR and other components of the corepressor complex. Consistent with this interpretation, overexpression of several functionally defined domains of N-CoR also relieve repression by nuclear receptors. N-CoR is distributed throughout the nucleus in a nonuniform pattern, and a subpopulation becomes concentrated into several discrete dot structures when highly expressed. RPD3 is also widely distributed throughout the nucleus in a nonuniform pattern. Simultaneous imaging of RPD3 and N-CoR suggest that a subset of each of these proteins colocalize, consistent with the existence of coactivator complexes containing both proteins. In addition, a substantial fraction of both N-CoR and mSin3 A/B appear to be independently distributed. These observations suggest that interactions between RPD3 and Sin3/N-CoR complexes may be dynamically regulated.
Mol Endocrinol 1997 Jun
PMID:Differential effects of nuclear receptor corepressor (N-CoR) expression levels on retinoic acid receptor-mediated repression support the existence of dynamically regulated corepressor complexes. 917 Dec 32

Steroid receptor antagonists, such as the antiestrogen tamoxifen or the antiprogestin RU486, can have inappropriate agonist-like effects in tissues and tumors. To explain this paradox we postulated that coactivators are inadvertently brought to the promoters of DNA-bound, antagonist-occupied receptors. The human (h) progesterone receptor (PR) hinge-hormone binding domain (H-HBD) was used as bait in a two-hybrid screen of a HeLa cDNA library, in which the yeast cells were treated with RU486. We have isolated and characterized two interesting steroid receptor-interacting proteins that regulate transcription in opposite directions. The first is L7/SPA, a previously described 27-kDa protein containing a basic region leucine zipper domain, having no known nuclear function. When coexpressed with tamoxifen-occupied estrogen receptors (hER) or RU486-occupied hPR or glucocorticoid receptors (hGR), L7/SPA increases the partial agonist activity of the antagonists by 3- to 10-fold, but it has no effect on agonist-mediated transcription. The interaction of L7/SPA with hPR maps to the hinge region, and indeed, the hPR hinge region squelches L7/SPA-dependent induction of antagonist-mediated transcription. Interestingly, pure antagonists that lack partial agonist effects, such as the antiestrogen ICI164,384 or the antiprogestin ZK98299, cannot be up-regulated by L7/SPA. We also isolated, cloned, and sequenced the human homolog (hN-CoR) of the 270-kDa mouse (m) thyroid/retinoic acid receptor corepressor. Binding of hN-CoR maps to the hPR-HBD. mN-CoR, and a related human corepressor, SMRT, suppress RU486 or tamoxifen-mediated partial agonist activity by more than 90%. This suppression is completely squelched by overexpression of the hPR H-HBD. Additionally, both corepressors reverse the antagonist-dependent transcriptional up-regulation produced by L7/SPA. Our data suggest that the direction of transcription by antagonist-occupied steroid receptors can be controlled by the ratio of coactivators to corepressors recruited to the transcription complex by promoter-bound receptors. In normal tissues and in hormone-resistant breast cancers in which the agonist activity of mixed antagonists predominates, steroid receptors may be preferentially bound by coactivators. This suggests a strategy by which such partial agonist activity can be eliminated and by which candidate receptor ligands can be screened for this activity.
Mol Endocrinol 1997 Jun
PMID:The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. 917 Dec 33

Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) are orphan receptors that belong to the steroid/thyroid hormone receptor (TR) superfamily and can repress the transcriptional activity of several target genes; however, the precise mechanism of this repression is unknown. Transfection of a Gal4 DNA-binding domain fused to the putative ligand-binding domain of COUP-TFI (Gal4-COUP-TFI) significantly represses the basal transcriptional activity of a reporter gene containing Gal4-binding sites. Cotransfection of COUP-TFI can relieve the Gal4-COUP-TFI repression in a dose-dependent manner. In contrast, COUP-TFI delta35, which lacks the repressor domain (the C-terminal 35 amino acids), fails to relieve this repression. This finding suggests that the repressor domain of COUP-TFI may squelch a limiting amount of corepressor in HeLa cells. In addition, increasing concentrations of TRbeta also can relieve the COUP-TFI repression in a hormone-sensitive manner. Similarly, overexpression of increasing concentration of COUP-TFI, but not COUP-TFI delta35, can squelch the silencing activity of the unliganded TRbeta. Collectively, these results indicate that COUP-TFI and TRbeta share a common corepressor(s) for their silencing activity. To determine which corepressor is involved in the COUP-TF-silencing activity, we used a yeast two-hybrid and in vitro GST pull-down assays to demonstrate that COUP-TFI can interact with the fragment of N-CoR (nuclear receptor-corepressor) encoding amino acids 921-2453 and the fragments of SMRT (silencing mediator for retinoic acid receptor and TR) encoding amino acids 29-564 and 565-1289, respectively. Interestingly, the fragment of SMRT encoding amino acids 1192-1495, which strongly interacts with TRbeta, interacts very weakly with COUP-TFI. Furthermore, overexpression of N-CoR or SMRT potentiates the silencing activity of COUP-TFI and can relieve the COUP-TFI-mediated squelching of Gal4-COUP-TFI activity. Therefore, our studies indicate that N-CoR and SMRT act as corepressors for the COUP-TFI silencing activity.
Mol Endocrinol 1997 Jun
PMID:Gene silencing by chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is mediated by transcriptional corepressors, nuclear receptor-corepressor (N-CoR) and silencing mediator for retinoic acid receptor and thyroid hormone receptor (SMRT). 917 Dec 35

To explore the role of retinoids in epidermal development, we recently targeted expression of a dominant-negative, retinoic acid receptor mutant (RAR alpha403) in the epidermis of transgenic mice and observed an unexpected loss of barrier function. In this paper, we demonstrate that transgenic mice expressing the RAR alpha403 transgene show attenuated responsiveness to topical application of all-trans retinoic acid, in agreement with our previous in vitro data. We also show that the vitamin D3 receptor is unaffected in its ability to transactivate in the presence of the dominant-negative RAR alpha403 transgene, indicating that the RAR alpha403 is unlikely to be functioning through a global sequestration of retinoid X receptors. Additionally, we show that the disruption of epidermal barrier function results in a dramatic 4 C drop in mean body surface temperature, probably accounting for the extremely high incidence of neonatal mortality in severely phenotypic pups. Some severely affected pups do survive and show a pronounced hyperkeratosis at postpartum day 4, consistent with previously documented effects of vitamin A deficiency. Biochemical analysis of the severely phenotypic neonates indicates elevated phospholipids and glycosylceramides in the stratum comeum, which results from altered lipid processing. Taken together with previous studies, these data provide strong evidence linking the retinoid-signaling pathway with modulation of lipid processing required for formation of epidermal barrier function.
Mol Endocrinol 1997 Jun
PMID:Inhibition of retinoid signaling in transgenic mice alters lipid processing and disrupts epidermal barrier function. 917 Dec 42


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