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

Mouse embryonal carcinoma F9 cells are pluripotent stem cells and differentiate into primitive endodermal cells upon treatment with retinoic acid (RA). We have recently shown that in F9 cells RA regulates gene expression of activin receptor type II (ActR-II), whose ligand is a potent differentiation agent. The present study examined the regulation of the newly cloned activin receptor type IIB (ActR-IIB) gene by RA. F9 cells expressed equal amounts of three ActR-IIB transcripts of 8.0, 7.5 and 4.0 kb. Both 9-cis-RA (c-RA) and all-trans-RA (t-RA) induced ActR-IIB gene expression in a dose-dependent manner. At 10(-9) M c-RA exerted no effect, while 10(-5) M c-RA increased the 8.0 kb ActR-IIB transcript about sevenfold. In contrast, t-RA induced the 8.0 kb ActR-IIB transcript fivefold at 10(-9) M and up to eightfold at 10(-5) M. The inductive effect on the 8.0 kb transcript was greater than that on the 7.5 kb transcript, and was least effective on the 4.0 kb transcript, suggesting that these three mRNA isoforms may originate from different promoters. Both cycloheximide and actinomycin D inhibited the inductive effect of t-RA on ActR-IIB gene expression, in contrast to ActR-II whose gene expression was not suppressed by cycloheximide but abolished by actinomycin D. Thus, endodermal differentiation of F9 cells is associated with activation of ActR-IIB gene and the mechanisms involved in the regulation of ActR-II and IIB gene expression are different.
J Mol Endocrinol 1995 Apr
PMID:Retinoic acid induces activin receptor IIB mRNA in F9 embryonal carcinoma cells. 761 12

The lactoferrin gene is highly expressed in many different tissues, and its expression is controlled by different regulators. In this report, we have defined a retinoic acid response element (RARE) in the 5'-flanking region of the lactoferrin gene promoter. The lactoferrin-RARE is composed of two AGGTCA-like motifs arranged as a direct repeat with 1-bp spacing (DR-1). A gel retardation assay demonstrated that it bound strongly with retinoid X receptor (RXR) homodimers and RXR-retinoic acid receptor (RAR) heterodimers as well as chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan receptor. In CV-1 cells, the lactoferrin-RARE linked with a heterologous thymidine kinase promoter was strongly activated by RXR homodimers in response to 9-cis-retinoic acid (9-cis-RA) but not to all-trans-RA. When the COUP-TF orphan receptor was cotransfected, the 9-cis-RA-induced RXR homodimer activity was strongly repressed. A unique feature of the lactoferrin-RARE is that it has an AGGTCA-like motif in common with an estrogen-responsive element (ERE). The composite RARE/ERE contributes to the functional interaction between retinoid receptors and the estrogen receptor (ER) and their ligands. In CV-1 cells, cotransfection of the retinoid and estrogen receptors led to mutual inhibition of the other's activity, while an RA-dependent inhibition of ER activity was observed in breast cancer cells. Furthermore, the lactoferrin-RARE/ERE showed differential transactivation activity in different cell types. RAs could activate the lactoferrin-RARE/ERE in human leukemia HL-60 cells and U937 cells but not in human breast cancer cells. By gel retardation analyses, we demonstrated that strong binding of the endogenous COUP-TF in breast cancer cells to the composite element contributed to diminished RA response in these cells. Thus, the lactoferrin-RARE/ERE functions as a signaling switch module that mediates multihormonal responsiveness in the regulation of lactoferrin gene expression.
Mol Cell Biol 1995 Aug
PMID:A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene. 762 14

Retinoids are reported to stimulate apolipoprotein (apo) A-I gene promoter activity (Rottman et al. 1991. Mol. Cell. Biol. 11: 3814-3820) and apoA-I protein secretion by monkey hepatocytes (Kaptein et al. 1993. Arterioscler. Thromb. 13: 1505-1514). In this study we have assessed the effects of retinoids on parameters of apoA-I biosynthesis in human cell lines. Caco-2 and HepG2 cells (human intestinal and hepatoma cell lines, respectively, both known to express and secrete apoA-I) were stably transfected with a reporter gene construct containing 1.3 kb of the 5-'flanking region of the human apoA-I gene linked to the firefly luciferase coding region. These cells were incubated for 48 h with 10 microM all-trans retinoic acid (RA) or 9-cis RA. The cells were then assayed for luciferase activity, for apoA-I mRNA level, and for secretion of apoA-I protein in the medium. Secretion of apoB was monitored as well. In Caco-2 cells, all-trans and 9-cis RA increased luciferase activity, mRNA content, and protein secretion by 40% to 80% above control. Strikingly, in HepG2 cells all-trans and 9-cis RA caused a more marked stimulation of luciferase activity (by 100-150%) but a weaker increase of mRNA content and protein secretion (by 25-30%). In contrast, apoB secretion was inhibited by the two retinoids in Caco-2 cells and not changed in HepG2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of human apolipoprotein A-I expression in Caco-2 and HepG2 cells by all-trans and 9-cis retinoic acids. 765 49

Retinoids induce myeloblastic leukemia (HL-60) cells to differentiate into granulocytes, which subsequently die by apoptosis. Retinoid action is mediated through at least two classes of nuclear receptors: retinoic acid receptors, which bind both all-trans retinoic acid and 9-cis retinoic acid, and retinoid X receptors, which bind only 9-cis retinoic acid. Using receptor-selective synthetic retinoids and HL-60 cell sublines with different retinoid responsiveness, we have investigated the contribution that each class of receptors makes to the processes of cellular differentiation and death. Our results demonstrate that ligand activation of retinoic acid receptors is sufficient to induce differentiation, whereas ligand activation of retinoid X receptors is essential for the induction of apoptosis in HL-60 cell lines.
Mol Cell Biol 1995 Jul
PMID:Activation of retinoid X receptors induces apoptosis in HL-60 cell lines. 779 61

The expression of all-trans-retinoic acid receptor (RAR) RNA was investigated by Northern blot and Reverse Transcription-Polymerase Chain Reaction in tissues and primary cultures of human thyrocytes. In normal and adenomatous samples the RAR alpha RNA was expressed, whereas the expression of RAR beta and gamma was undetectable. In carcinoma samples RAR alpha RNA expression could decline, whereas the RAR beta RNA expression could become detectable. TSH and retinoic acid did not significantly modify RAR alpha mRNA levels, whereas RA caused a significant decrease in basal and TSH-induced thyroid peroxidase (TPO) mRNA levels, and a decrease in DNA synthesis. These results demonstrate that RAR alpha gene is predominantly expressed in human thyrocytes, and suggest a molecular link between this gene and the negative regulation by RA of proliferation and function of follicular cells.
Biochem Mol Biol Int 1994 Aug
PMID:Expression of all-trans-retinoic acid receptor RNA in human thyroid cells. 780 36

F9 embryonic teratocarcinoma stem cells differentiate into an epithelial cell type called extraembryonic endoderm when treated with retinoic acid (RA), a derivative of retinol (vitamin A). This differentiation is presumably mediated through the actions of retinoid receptors, the RARs and RXRs. To delineate the functions of each of the different retinoid receptors in this model system, we have generated F9 cell lines in which both copies of either the RAR alpha gene or the RAR gamma gene are disrupted by homologous recombination. The absence of RAR alpha is associated with a reduction in the RA-induced expression of both the CRABP-II and Hoxb-1 (formerly 2.9) genes. The absence of RAR gamma is associated with a loss of the RA-inducible expression of the Hoxa-1 (formerly Hox-1.6), Hoxa-3 (formerly Hox-1.5), laminin B1, collagen IV (alpha 1), GATA-4, and BMP-2 genes. Furthermore, the loss of RAR gamma is associated with a reduction in the metabolism of all-trans-RA to more polar derivatives, while the loss of RAR alpha is associated with an increase in metabolism of RA relative to wild-type F9 cells. Thus, each of these RARs exhibits some specificity with respect to the regulation of differentiation-specific gene expression. These results provide an explanation for the expression of multiple RAR types within one cell type and suggest that each RAR has specific functions.
Mol Cell Biol 1995 Feb
PMID:Targeted disruption of retinoic acid receptor alpha (RAR alpha) and RAR gamma results in receptor-specific alterations in retinoic acid-mediated differentiation and retinoic acid metabolism. 782 50

Previous results from our laboratory gave evidence that safe doses of vitamin A were very effective in protecting rats from adriamycin-induced oxidative stress and lethal cardiotoxicity (Tesoriere, L. et al. (1994) J. Pharmacol. Experim. Ther. 269, 430-436). This was an incentive also to evaluate whether or not vitamin A affected the antitumor activity of adriamycin. K562 human erythroleukemia cells were exposed to adriamycin or to adriamycin plus vitamin A. Presence of 2.5 to 15 microM all-trans retinol in the cell culture did not impair the cytotoxicity of adriamycin. Rather, an enhanced cell death was observed when cell colony was exposed to both compounds. Additional assays showed that all-trans retinol counteracted the lipoperoxide formation, assayed as malondialdehyde, induced in cell cultures by the redox cycling activity of adriamycin. These data strongly encourage a new therapeuthical approach with safe doses of vitamin A as an adjuvant in cancer chemotherapy.
Biochem Mol Biol Int 1994 Sep
PMID:Vitamin A preserves the cytotoxic activity of adriamycin while counteracting its peroxidative effects in human leukemic cells in vitro. 784 45

Autologous regulation of steroid receptors by their cognate ligands has been demonstrated for a number of nuclear receptor family members. To determine the molecular mechanism for glucocorticoid receptor (GR) autoregulation, the expression of glucocorticoid receptor mRNA and protein levels were examined in the mouse AtT-20 pituitary tumor cell line. The expression of c-jun and c-fos mRNA and protein was also examined in the same cell extracts. A rapid down-regulation of the GR protein was observed after treatment with the glucocorticoid analog, triamcinolone acetonide (TA). An oscillatory, parallel regulation of both GR and c-jun mRNA levels occurred. In contrast, POMC mRNA levels remained at a stable, low level during chronic TA treatment. Dose-response analyses also revealed a coordinate down-regulation of GR and c-jun (but not POMC or c-fos) mRNA levels. FOS protein levels were unaffected by TA treatment. Surprisingly, JUN protein levels were increased by TA, even when the c-jun mRNA levels were decreasing. Perhaps a derepression of c-jun mRNA translation occurs after TA treatment, and this may be due to GR/JUN heteromer formation interfering with JUN repression of c-jun mRNA translation. The effect of TA on GR and c-jun gene expression was a primary effect, as it occurred rapidly and was not inhibited by cycloheximide (CHX). Nuclear run-on transcription assays revealed a rapid (15 min) down-regulation in both GR and c-jun gene transcription rates, while POMC gene transcription was unaffected at this early time. Treatment of AtT-20 cells with all-trans retinoic acid gave different kinetics for GR and c-jun mRNA regulation than obtained with TA; however, the GR and c-jun mRNA levels were still coordinately regulated after retinoic acid treatment. Based upon these data, the promoter structures of the GR and c-jun genes, and previously published results, a novel mechanism for the coupled regulation of GR and c-jun transcription, via a direct transcriptional interference with AP-1 (FOS/JUN) activity, is proposed.
Mol Endocrinol 1994 Oct
PMID:Coordinate regulation of glucocorticoid receptor and c-jun mRNA levels: evidence for cross-talk between two signaling pathways' at the transcriptional level. 785 51

The ligand-binding domains (LBDs) of the thyroid/retinoid receptor gene subfamily contain a series of heptad motifs important for dimeric interactions. This subfamily includes thyroid hormone receptors (T3Rs), all-trans retinoic acid (RA) receptors (RARs), 9-cis RA receptors (RARs and retinoid X receptors [RXRs]), the 1,25-dihydroxyvitamin D3 receptor (VDR), and the receptors that modulate the peroxisomal beta-oxidation pathway (PPARs). These receptors bind to their DNA response elements in vitro as heterodimers with the RXRs. Unliganded receptors in vivo, in particular the T3Rs, can mediate gene silencing and ligand converts these receptors into a transcriptionally active form. The in vivo interactions of these receptors with RXR were studied by using a GAL4-RXR chimera containing the yeast GAL4 DNA-binding domain and the LBD of RXR beta. GAL4-RXR activates transcription from GAL4 response elements in the presence of 9-cis RA. Unliganded T3R, which does not bind or activate GAL4 elements, represses the activation of GAL4-RXR by 9-cis RA in HeLa cells. However, addition of T3 alone leads to transcriptional activation. These findings suggest that T3R can repress or activate transcription while tethered to the LBD of GAL4-RXR and that heterodimerization can occur in vivo without stabilization by hormone response elements. Similar ligand-dependent activation was observed in HeLa cells expressing RAR, VDR, or PPAR and in GH4C1 cells from endogenous receptors. Replacement of the last 17 amino acids of the LBD of RXRbeta with the 90-amino-acid transactivating domain of the herpes simplex virus VP16 protein leads to a GAL4 constitutive activator that is repressed by wild-type T3R but not by a ninth heptad mutant that does not form heterodimers. This finding suggests that the ninth heptad or T3R is important for gene silencing and that the LBD of RXR does not exhibit silencing activity. This conclusion was verified with GAL4-LBD chimeras and with wild-type receptors in assays using appropriate response elements. These studies indicate that the LBD has diverse functional roles in gene regulation.
Mol Cell Biol 1995 Mar
PMID:The ligand-binding domains of the thyroid hormone/retinoid receptor gene subfamily function in vivo to mediate heterodimerization, gene silencing, and transactivation. 786 71

Transforming growth factor-beta (TGF-beta)-stimulated collagen production plays an important role in the pathogenesis of the fibrotic response seen in chronic inflammatory lung disorders. Retinoids are vitamin A analogues that are potent immunomodulators and have been shown to modulate stromal cell collagen production in a variety of nonpulmonary systems. We hypothesized that retinoids might also modulate lung fibroblast collagen production. To test this hypothesis, we determined whether all-trans retinoic acid (RA) and several other retinoid compounds regulate the production of types I and III collagen by unstimulated and TGF-beta 1-stimulated human lung fibroblasts. Unstimulated cells produced modest quantities of types I and III collagen, and TGF-beta 1 increased the production of these matrix molecules 2- to 4-fold. Preincubation with 10(-5) M RA caused a significant decrease in the basal levels of types I and III collagen produced by these cells. RA preincubation also totally abrogated the collagen inductive effects of TGF-beta 1. At 10(-5) M, RA preincubation caused a 97% decrease in the stimulation of type I collagen and a 115% decrease in the stimulation of type III collagen caused by TGF-beta 1. These inhibitory effects were dose dependent. Significant inhibition of type I and III collagen production was appreciated with doses of RA as low as 10(-9) and 10(-8), respectively. These inhibitory effects were not unique to RA since 13-cis-retinoic acid, 9-cis-retinoic acid, etretinate, all-trans etretin, and the water-soluble retinoids, retinoyl beta-glucuronide and retinyl-beta-glucuronide, also inhibited TGF-beta 1-stimulated type I collagen production.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Mar
PMID:Retinoic acid inhibition of transforming growth factor-beta-induced collagen production by human lung fibroblasts. 787 95


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