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

Retinoic acid (RA) modulates the growth and differentiation of various normal and malignant cells. These effects are most likely mediated by changes in gene expression. Genes whose expression is modulated by RA may be useful as markers of growth responsiveness to retinoids. Using differential cDNA cloning we identified 10 genes regulated by RA in the head and neck squamous cell carcinoma cell line MDA886Ln. Keratin (K) 13 gene expression was the gene expression most related to the degree of sensitivity of growth to RA, as K13 was not expressed in a series of RA-resistant cell lines. Our data suggest that low K13 expression may be mechanistically related to resistance to RA-induced growth inhibition.
Mol Carcinog 1996 May
PMID:Coordinate control of growth and cytokeratin 13 expression by retinoic acid. 863 95

Retinoic acid (RA) regulation of human cathepsin D (cath D) gene expression was investigated in this study. RA enhanced cath D mRNA levels in a concentration-dependent manner in MCF-7 human breast carcinoma cells. RA regulation of cath D mRNA levels was predominantly transcriptional because RA also increased cath D gene core promoter activity. Upon further characterization of the core promoter we localized RA responsive region to proximal 112-bp. The proximal 112-bp region of cath D gene promoter harbours several retinoid response element (RARE)-like sequences. In gel shift experiments the sequence between -100 and -74 nucleotides in the CD112 region carrying imperfect direct repeat and a palindrome competed with RARE for binding to RAR/RXRs. These sequences, however, exhibited binding to protein complexes which could not be competed with unlabeled RARE or up-shifted with RAR/RXR-specific antibodies. We conclude that RA predominantly regulates cath D gene expression from the proximal 112-bp of the promoter region, but this regulation appears indirect.
J Steroid Biochem Mol Biol 1996 Mar
PMID:Retinoid regulation of human cathepsin D gene expression. 863 64

Retinoic acid (RA) inhibits adipocyte differentiation of 3T3-L1 preadipocytes but is effective only early in adipogenesis. RA prevented induction of the adipogenic factors PPARgamma and C/EBPalpha. Using receptor-specific ligands, we determined that the effects of RA were mediated by liganded RA receptors (RARs) rather than retinoid X receptors. Preadipocytes expressed primarily RARalpha and RARgamma; during adipocyte differentiation, RARalpha gene expression was nearly constant, whereas RARgamma1 mRNA and protein levels dramatically decreased. Ectopic expression of RARgamma1 extended the period of effectiveness of RA by 24 to 48h; RARalpha expression had a similar effect, suggesting functional redundancy of RAR subtypes. Remarkably, RA inhibited differentiation when added after PPARgamma1 and PPARgamma2 proteins had already been expressed and resulted in the loss of PPARgamma proteins from cells. By 72 to 96 h after the induction of differentiation, RA failed to prevent differentiation of even ectopic-RAR-expressing cells. Thus, the unresponsiveness of 3T3-L1 preadipocytes to RA after the induction of differentiation is initially due to the reduction in cellular RAR concentration rather than to the induction of PPARgamma. At later times cells continue along the differentiation pathway in a manner which is RA and RAR independent.
Mol Cell Biol 1996 Apr
PMID:Distinct stages in adipogenesis revealed by retinoid inhibition of differentiation after induction of PPARgamma. 865 31

Considering the link between plasma high-density lipoprotein (HDL) cholesterol levels and a protective effect against coronary artery disease as well as the suggested beneficial effects of retinoids on the production of the major HDL apolipoprotein (apo), apo A-I, the goal of this study was to analyze the influence of retinoids on the expression of apo A-II, the other major HDL protein. Retinoic acid (RA) derivatives have a direct effect on hepatic apo A-II production, since all-trans (at) RA induces apo A-II mRNA levels and apo A-II secretion in primary cultures of human hepatocytes. In the HepG2 human hepatoblastoma cell line, both at-RA and 9-cis RA as well as the retinoid X receptor (RXR)-specific agonist LGD 1069, but not the RA receptor (RAR) agonist ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-pro penyl]-benzoic acid (TTNPB), induce apo A-II mRNA levels. Transient-transfection experiments with a reporter construct driven by the human apo A-II gene promoter indicated that 9-cis RA and at-RA, as well as the RXR agonists LGD 1069 and LG 100268, induced apo A-II gene expression at the transcriptional level. Only minimal effects of the RAR agonist TTNPB were observed on the apo A-II promoter reporter construct. Unilateral deletions and site-directed mutagenesis identified the J site of the apo A-II promoter mediating the responsiveness to RA. This element contains two imperfect half-sites spaced by 1 oligonucleotide. Cotransfection assays in combination with the use of RXR or RAR agonists showed that RXR but not RAR transactivates the apo A-II promoter through this element. By contrast, RAR inhibits the inductive effects of RXR on the apo A-II J site in a dose-dependent fashion. Gel retardation assays demonstrated that RXR homodimers bind, although with a lower affinity than RAR-RXR heterodimers, to the AH-RXR response element. In conclusion, retinoids induce hepatic apo A-II production at the transcriptional level via the interaction of RXR with an element in the J site containing two imperfect half-sites spaced by 1 oligonucleotide, thereby demonstrating an important role of RXR in controlling human lipoprotein metabolism. Since the J site also confers responsiveness of the apo A-II gene to fibrates and fatty acids via the activation of peroxisome proliferator-activated receptor-RXR heterodimers, this site can be considered a plurimetabolic response element.
Mol Cell Biol 1996 Jul
PMID:Retinoids increase human apolipoprotein A-11 expression through activation of the retinoid X receptor but not the retinoic acid receptor. 866 50

Retinoic acid receptor (RAR) and retinoid X receptor (RXR) form heterodimers and regulate retinoid-mediated gene expression. We studied binding of RXR- and RAR-selective ligands to the RXR-RAR heterodimer and subsequent transcription. In limited proteolysis analyses, both RXR and RAR in the heterodimer bound their respective ligands and underwent a conformational change in the presence of a retinoic acid-responsive element. In reporter analyses, the RAR ligand (but not the RXR ligand), when added singly, activated transcription, but coaddition of the two ligands led to synergistic activation of transcription. This activation required the AF-2 domain of both RXR and RAR. Genomic footprinting analysis was performed with P19 embryonal carcinoma cells, in which transcription of the RARbeta gene is induced upon retinoid addition. Paralleling the reporter activation data, only the RAR ligand induced in vivo occupancy of the RARbeta2 promoter when added singly. However, at suboptimal concentrations of RAR ligand, coaddition of the RXR ligand increased the stability of promoter occupancy. Thus, liganded RXR and RAR both participate in transcription. Finally, when these ligands were tested for teratogenic effects on zebra fish and Xenopus embryos, we found that coadministration of the RXR and RAR ligands caused more severe abnormalities in these embryos than either ligand alone, providing biological support for the synergistic action of the two ligands.
Mol Cell Biol 1997 Feb
PMID:Retinoid X receptor (RXR) within the RXR-retinoic acid receptor heterodimer binds its ligand and enhances retinoid-dependent gene expression. 900 Dec 18

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

Retinoic acid (RA) inhibition of breast cancer cell growth is associated with an accumulation of cells in G1 phase of the cell cycle. We have investigated the effects of RA on the expression and activity of cell cycle-regulatory proteins in MCF-7 human breast cancer cells. Flow cytometry analysis of MCF-7 cells treated with RA revealed a decrease in the percentage of cells in S phase by 48 h, which was maximal by 72 h. Phosphorylation of the retinoblastoma protein (pRb) was partially reduced in RA-treated cells accompanied by a decrease in the level of retinoblastoma protein. Expression of the cyclin D1 transcript was reduced by 48 h and cyclin-dependent kinase 2 (cdk2) mRNA levels declined within 8 h posttreatment followed by a decrease in cyclin D1 and cdk2 protein levels. Message and protein levels of cdk4 and cdc2 were not affected by RA. While cdk4 activity was similar in control and RA-treated cells, cdk2 activity began to decrease within 48 h of exposure to RA and was profoundly reduced after 72 h. This reduced activity was associated with decreased phosphorylation of cdk2. The decrease in cdk2 activity occurred in the absence of RA-mediated increases in the levels of the cdk inhibitors p21 and p27. However, assays of cdk2 from pooled lysates from RA-treated and control cells showed that RA-treated cells contain a cdk2-inhibitory activity. Our results show that RA inhibits cell cycle progression of MCF-7 cells by inhibiting cdk2 mRNA and protein production and by decreasing cdk2 activity.
Mol Endocrinol 1997 Aug
PMID:CDK2 is a target for retinoic acid-mediated growth inhibition in MCF-7 human breast cancer cells. 925 11

In rats, vaginal epithelium shows cyclic changes with an alternating pattern of keratinization under estrogen control and mucification under progesterone control. Since retinoids suppress keratinizing differentiation, in this paper we studied the expression of the major retinoid receptors normally present in keratinizing squamous epithelia: RAR alpha, RAR gamma and RXR alpha. In cyclic rats and steroid-treated ovariectomized rats, RXR alpha and RAR gamma were detected in basal and suprabasal cells while RAR alpha was mainly localized in suprabasal cells. No changes in RAR gamma expression were observed in correlation with ovarian steroids. During diestrus and in ovariectomized rats, the superficial cuboid cells expressed the three receptors. In the uterine epithelium, RAR alpha, RAR gamma and RXR alpha expression was induced by estrogens. Retinoic acid treatment did not modify retinoid receptor expression in vaginal and uterine epithelia. These data suggest specific roles for the different receptors in the complex process of vaginal epithelium proliferation and differentiation under estrogens and retinoic acid control.
Mol Cell Endocrinol 1997 Sep 19
PMID:Retinoid receptors in rat vaginal and uterine epithelia: changes with ovarian steroids. 932 51

Levels of acylphosphatase isoenzymes and free intracellular calcium have been investigated in cultured SH-SY5Y human neuroblastoma cells under stimulation with all-trans retinoic acid and phorbol-12-myristate-13-acetate. Under these conditions morphological and functional characteristics demonstrated the differentiation of SH-SY5Y cells towards neuronal phenotype. Retinoic acid treatment caused a progressive and synchronous increase of the organ common-type acylphosphatase and of free intracellular calcium but not of the muscle-type acylphosphatase. Phorbol-12-myristate-13-acetate treatment gave rise to a peak of the muscle-type acylphosphatase levels during the early differentiation stage whereas organ common-type isoenzyme and free calcium levels show a pattern similar to that observed in retinoic acid-treated cells. These evidences indicate that the two acylphosphatase isoenzymes play different roles in SH-SY5Y differentiation and that during this process the expression of organ common-type acylphosphatase increases in a synchronous way with intracellular free calcium concentration.
Biochem Mol Biol Int 1997 Oct
PMID:Alteration of intracellular free calcium and acylphosphatase levels in differentiating SH-SY5Y neuroblastoma cells. 935 82

Retinoic acid (RA) stimulates transcription from the retinoic acid receptor beta2 (RARbeta2) promoter in mammalian embryonal cells. Evidence by in vivo deoxyribonuclease I (DNase I) hypersensitivity assay indicates that RA treatment of these cells results in an alteration of chromatin structure in and near the promoter. To study the role of chromatin in RA-activated transcription, we assembled the RARbeta2 promoter into chromatin in Xenopus oocytes. Ectopic expression of RAR and retinoid X receptor (RXR) enhanced transcription without ligand, irrespective of whether chromatin was assembled in a replication-dependent or -independent manner, although ligand addition led to a further, marked increase in transcription. Moreover, expression of RAR and RXR, without ligand addition, induced DNase I-hypersensitive sites in the chromatin-assembled promoter. Furthermore, expression of RAR and RXR in oocytes led to local disruption of chromatin assembled over the promoter without ligand. Similar ligand-independent, but RXR/RAR-dependent nucleosomal disruption was observed in an in vitro chromatin reconstitution system using Drosophila embryonic extracts. Thus, unliganded receptors expressed in oocytes are capable of accessing to the chromatin-assembled promoter and activating transcription without ligand, indicating that chromatin assembly per se is not sufficient to reproduce ligand-dependent chromatin changes and promoter activation seen in mammalian cells. The oocyte system may serve as a model to study mechanisms of RA-dependent alterations of chromatin structure.
Mol Endocrinol 1998 Mar
PMID:Retinoid receptor-induced alteration of the chromatin assembled on a ligand-responsive promoter in Xenopus oocytes. 951 49


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