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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), a vitamin A derivative is known to have a number of effects on the immune system such as inducing cytotoxic T-lymphocytes in vivo and inducing the rejection of skin grafts. However, the molecular mechanisms of these actions are unclear. The retinoic acid receptors which belong to the steroid/thyroid receptor superfamily, are known to bind to regulatory elements of certain genes thereby regulating gene transcription. To determine if expression of retinoic acid receptors in vivo under normal physiological conditions is also regulating genes involved in immunological function, we assayed the human retinoic acid receptor gamma gene driven by a T-cell specific lck-promoter in transgenic mice. Using FACS analysis, we showed that mice expressing the RAR gamma-transgene had significantly increased numbers of CD4-/CD8+ cells compared to controls.
Mol Biol Rep 1993 Feb
PMID:Transcription of retinoic acid receptor genes in transgenic mice increases CD8 T-cell subset. 838 93

We have evaluated the effects of retinoic acid as a differentiating agent on two pluripotential mesenchymal stem cell lines, the mouse cell line C3H-10T1/2 (10T1/2), which has the capacity to differentiate in vitro into myoblasts, adipocytes, chondrocytes, and osteoblasts, and the rat cell line ROB-C26 (C26), which can, in culture, give rise to adipocytes, myoblasts, and osteoblasts. Retinoic acid (10(-6) M) reduces the incidence of myoblast and adipocyte formation and induces or increases alkaline phosphatase expression and responsiveness to PTH, two indicators of the osteoblastic phenotype. Because transforming growth factor-beta (TGF beta) superfamily members, including the different TGF beta isoforms and the bone morphogenetic proteins (BMPs), are thought to play a role in regulating bone and cartilage formation, and because exogenous TGF beta and BMP-2 have already been found to modulate osteoblastic differentiation of C26 and 10T1/2 cells, we evaluated the endogenous expression of these factors in both cell lines cultured in the presence or absence of retinoic acid. Our data show that C26 and 10T1/2 cells constitutively express a broad spectrum of TGF beta superfamily members. However, this pattern of expression is dramatically altered in response to retinoic acid. Specifically, expression of TGF beta 1 and especially TGF beta 2 is strongly increased, whereas TGF beta 3 expression is down-regulated. These changes are accompanied by a striking decline in TGF beta receptor expression levels at the cell surface. Furthermore, BMP-2 and -4 expression are decreased after treatment with retinoic acid, whereas vgr-1/BMP-6 expression is induced in C26 cells, but decreased in 10T1/2 cells. These results clearly show a dynamic changing pattern of TGF beta superfamily expression consequent to the induction of osteogenic differentiation and provide the first indication that TGF beta receptor down-regulation may be an essential part of this differentiation process. These data also establish the C26 and 10T1/2 cell lines as convenient in vitro model systems for exploring the autoregulation of osteogenic differentiation by members of the TGF beta superfamily.
Mol Endocrinol 1993 Feb
PMID:Modulation of expression and cell surface binding of members of the transforming growth factor-beta superfamily during retinoic acid-induced osteoblastic differentiation of multipotential mesenchymal cells. 838 38

Retinoic acid (RA) strongly inhibits proliferation of the estrogen (E2)-dependent human breast cancer cell lines MCF7, T47D, and ZR75-1, but not the E2-independent and E2 receptor (ER)-negative lines MDA-MB231, MDA-MB468, BT20 and Hs578T. The specific sensitivity of the E2-dependent cell lines seems not to be caused by an inhibitory effect of RA on ER functioning since RA inhibited the proliferative response not only to E2 but also to insulin. Furthermore, endogenous RA receptors (RARs) hardly impaired transcriptional activation of an E2 responsive element-tk-CAT reporter construct. RAR alpha mRNA was highly expressed in the RA-responsive lines, but not in the unresponsive lines, except BT20. With the exception of Hs578T, also RAR beta mRNA expression was low in the unresponsive lines. While in the dependent lines and Hs578T RA activated RA responsive element-dependent transcriptional activity, this response was very low in MDA-MB231, MDA-MB468, and BT20, suggesting that the RA resistance of these latter three ER-negative lines is due to underexpression of functional RARs. Our results suggest that the loss of functional RARs may be a frequent event, leading to RA unresponsiveness of ER-negative breast cancer cells. This implies that both the steroid and retinoid receptor status of breast tumors may be used to predict a successful treatment with retinoids.
Mol Cell Endocrinol 1993 Feb
PMID:Retinoic acid resistance of estradiol-independent breast cancer cells coincides with diminished retinoic acid receptor function. 838 11

Retinoic acid receptors (RARs) are ligand-activated nuclear transcription factors that belong to the steroid-thyroid hormone receptor superfamily. We have used the transient transfection of a retinoic acid-responsive reporter plasmid (RARECAT) to investigate the potential interactions between the retinoic acid (RA) and cAMP signaling pathways. Cotransfections of expression plasmids for the catalytic (C) subunits of cAMP-dependent protein kinase with RARECAT showed ligand-independent activation in both CV-1 and HeLa cells and a further 2-fold increase in RARECAT activity in the presence of RA. In CV-1 cells, cotransfections of the expression plasmids for RAR and the C-subunits produced increases in RARECAT activity (12- and 8-fold in the absence of ligand and 21- and 15-fold in the presence of RA for the C alpha- and C beta-isoforms, respectively). Cotransfections of both the C beta-subunit and RAR expression plasmids in HeLa cells produced 22- and 114-fold increases in RARECAT activity in the absence and presence of RA, respectively. These results provide evidence to suggest that the RA and cAMP signaling pathways are coupled, and signaling cross-talk may occur through the direct phosphorylation of RARs by the C-subunit as indicated by in vitro phosphorylation of the receptor.
Mol Endocrinol 1993 Apr
PMID:Modification of the retinoic acid signaling pathway by the catalytic subunit of protein kinase-A. 838 97

We have investigated the mechanism underlying repression of calcitonin/calcitonin gene-related peptide (CT/CGRP) gene expression by retinoic acid. Retinoic acid treatment of the CA77 thyroid C-cell line decreased CT/CGRP promoter activity two- to threefold, which correlates well with the decrease in calcitonin and CGRP mRNA levels. Repression is mediated through the nuclear retinoic acid receptors (RAR) on the basis of the retinoid specificity, the sensitivity of repression (half-maximal repression at 0.2 nM), and the additional repression caused by cotransfection of an alpha-RAR expression vector. The sequences required for retinoic acid repression were localized to an 18-bp element containing cell-specific enhancer activity. The enhancer binds helix-loop-helix (HLH) and octamer transcription factors that act synergistically to activate transcription. Retinoic acid repression requires both these factors since mutations in either motif resulted in the loss of repression. Furthermore, repression was observed only in cell lines containing enhancer activity. We have used electrophoretic mobility shift assays to show that repression does not involve direct DNA binding of RAR or RAR-retinoid X receptor heterodimers. Instead, repression appears to involve interactions with the stimulatory enhancer factors. Following retinoic acid treatment, there was a specific decrease in an enhancer complex containing both HLH and octamer proteins. Formation of the HLH-octamer complex was also specifically blocked by the addition of exogenous RAR-retinoid X receptor protein. These results demonstrate that RAR can repress CT/CGRP gene transcription by interfering with combinatorial activation by cell-specific HLH and octamer proteins.
Mol Cell Biol 1993 Oct
PMID:Retinoic acid repression of cell-specific helix-loop-helix-octamer activation of the calcitonin/calcitonin gene-related peptide enhancer. 841 10

Retinoic acid (RA) treatment of human embryonal carcinoma (EC) NTera-2 (NT2) cells induces expression of major histocompatibility complex (MHC) class I and beta-2 microglobulin surface molecules. We found that this induction was accompanied by increased levels of MHC class I mRNA, which was attributable to the activation of the two conserved upstream enhancers, region I (NF-kappa B like) and region II. This activation coincided with the induction of nuclear factor binding activities specific for the two enhancers. Region I binding activity was not present in undifferentiated NT2 cells, but binding of an NF-kappa B heterodimer, p50-p65, was induced following RA treatment. The p50-p65 heterodimer was produced as a result of de novo induction of p50 and p65 mRNAs. Region II binding activity was present in undifferentiated cells at low levels but was greatly augmented by RA treatment because of activation of a nuclear hormone receptor heterodimer composed of the retinoid X receptor (RXR beta) and the RA receptor (RAR beta). The RXR beta-RAR beta heterodimer also bound RA responsive elements present in other genes which are likely to be involved in RA triggering of EC cell differentiation. Furthermore, transfection of p50 and p65 into undifferentiated NT2 cells synergistically activated region I-dependent MHC class I reporter activity. A similar increase in MHC class I reporter activity was demonstrated by cotransfection of RXR beta and RAR beta. These data show that following RA treatment, heterodimers of two transcription factor families are induced to bind to the MHC enhancers, which at least partly accounts for RA induction of MHC class I expression in NT2 EC cells.
Mol Cell Biol 1993 Oct
PMID:Retinoic acid induction of major histocompatibility complex class I genes in NTera-2 embryonal carcinoma cells involves induction of NF-kappa B (p50-p65) and retinoic acid receptor beta-retinoid X receptor beta heterodimers. 841 17

We report the cDNA cloning and characterization of mouse GATA-4, a new member of the family of zinc finger transcription factors that bind a core GATA motif. GATA-4 cDNA was identified by screening a 6.5-day mouse embryo library with oligonucleotide probes corresponding to a highly conserved region of the finger domains. Like other proteins of the family, GATA-4 is approximately 50 kDa in size and contains two zinc finger domains of the form C-X-N-C-(X17)-C-N-X-C. Cotransfection assays in heterologous cells demonstrate that GATA-4 trans activates reporter constructs containing GATA promoter elements. Northern (RNA) analysis and in situ hybridization show that GATA-4 mRNA is expressed in the heart, intestinal epithelium, primitive endoderm, and gonads. Retinoic acid-induced differentiation of mouse F9 cells into visceral or parietal endoderm is accompanied by increased expression of GATA-4 mRNA and protein. In vitro differentiation of embryonic stem cells into embryoid bodies is also associated with increased GATA-4 expression. We conclude that GATA-4 is a tissue-specific, retinoic acid-inducible, and developmentally regulated transcription factor. On the basis of its tissue distribution, we speculate that GATA-4 plays a role in gene expression in the heart, intestinal epithelium, primitive endoderm, and gonads.
Mol Cell Biol 1993 Apr
PMID:Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart. 845 8

Retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers bind to cognate response elements in vitro more efficiently than do RAR or RXR homodimers, and both RAR and RXR partners have been shown to activate various promoters in transiently transfected cells. We have now investigated whether ligand-dependent activation of both heterodimeric partners is involved in induced expression of endogenous RA-responsive genes and in P19 and F9 cell differentiation. On their own, low concentrations of retinoids selective for either RAR alpha, RAR beta, or RAR gamma did not induce or very inefficiently induced the expression of several RA target genes or triggered differentiation. An RXR-specific synthetic retinoid was similarly inefficient at any concentration. In contrast, at the same concentrations, various combinations of RAR (RAR alpha, RAR beta, or RAR gamma) and RXR selective retinoids resulted in synergistic induction of all retinoic acid (RA) target genes examined, as well as in cell differentiation. However, the magnitude of this synergistic activation varied depending on both the RAR-RXR combination and the promoter context of the responsive genes. Promiscuous activation of the three RARs, or concomitant activation of RAR alpha and RAR gamma, at selective retinoid concentrations also resulted in induction of gene expression and cell differentiation. Taken together, our results are consistent with the conclusion that the RAR and RXR partners of RAR-RXR heterodimers can synergistically activate transcription of RA-responsive genes and can induce differentiation of P19 and F9 cells. Our results also indicate that there is a significant degree of functional redundancy between the three RAR types which, however, varies with the nature of the RA target genes.
Mol Cell Biol 1995 Dec
PMID:Synergistic activation of retinoic acid (RA)-responsive genes and induction of embryonal carcinoma cell differentiation by an RA receptor alpha (RAR alpha)-, RAR beta-, or RAR gamma-selective ligand in combination with a retinoid X receptor-specific ligand. 852 12

Retinoic acid receptors (RARs) are nuclear transcription factors that are activated by all-trans-retinoic acid or 9-cis-retinoic acid and are found in all tissues but predominantly in developing fetus, dividing tumor cells, and adult skin. Three forms of these receptors, alpha, beta, and gamma, have been described. In this paper we report the presence of RAR alpha and beta determined by hybridization with anti-sense messenger RNA, and histochemical localization of the three forms of RARs using monospecific polyclonal antibodies in various tissues of early human embryos. In a 54-day-old embryo, RAR alpha was expressed primarily in the liver and the brain, with somewhat lesser expression in the intestine. RAR beta was the highest in the brain, followed by a restricted expression in the intestine and the liver. Other organs, i.e., adrenal, kidney, and testis, did not show measurable amounts of RAR beta. The immunohistochemical localization in anterior sections of a 43-day-old embryo indicated that RAR alpha was present in the neuroepithelial cells and in cells lining the primitive pharyngeal sac, dorsal aorta, and pericardium. RAR beta was somewhat less prevalent in same tissues, whereas the expression of RAR gamma was the lowest of the three RARs in any tissues examined. Results indicated that RAR alpha and beta appear at early stages of human embryonic development and their expression is restricted to certain types of tissues.
Exp Mol Pathol 1995 Jun
PMID:Localization of retinoic acid receptors in anterior-human embryo. 861 22

An airway epithelial mucous goblet cell line would be useful towards understanding mechanisms underlying the common problem of respiratory mucus hypersecretion. SPOC1 is a novel rat tracheal epithelial (RTE) cell line that developed cytologic features suggestive of mucous goblet cells when grown in tracheal grafts in vivo (Am. J. Respir. Cell Mol. Biol. 1995; 12:385-395). Our aims were to determine whether SPOC1 cells were capable of mucin synthesis and to directly compare mucin production by SPOC1 cells and RTE cells. Towards this end, we validated the use of monoclonal antibody (mAb) RTE11 (Exp. Lung Res. 1992; 18:323-342) as an immunologic probe for rat airway secretory mucin. Our results strongly suggest that mAb RTE11 detects a carbohydrate antigen that is a sensitive and specific marker for rat tracheobronchial secretory mucin. SPOC1 cells in tracheal grafts in vivo contained granules with ultrastructural features similar to mucous granules in normal rat airway goblet cells and they were strongly stained by mAb RTE11. Retinoic acid (RA) and culture on porous supports are known to profoundly modify airway epithelial cell phenotype in vitro. Expression of several retinoid-responsive proteins was similar in cultured SPOC1 and primary RTE cells, but major differences in mucin production were noted. Primary RTE cells in vitro only made mucin when grown on porous supports in the presence of RA, whereas SPOC1 cells produced mucin when grown on plastic or glass surfaces and even in the absence of RA. Interestingly, RA enhanced mucin secretion by SPOC1 cells during the early plateau stage of culture but there were no differences due to RA late in the culture period. SPOC1 cells are capable of mucin production and will be a useful tool for studying select aspects of airway secretory cell differentiation and function.
Am J Respir Cell Mol Biol 1996 Feb
PMID:Mucin production by SPOC1 cells--an immortalized rat tracheal epithelial cell line. 863 Feb 64


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