scholarly journals Distinct retinoid X receptor-retinoic acid receptor heterodimers are differentially involved in the control of expression of retinoid target genes in F9 embryonal carcinoma cells.

1997 ◽  
Vol 17 (6) ◽  
pp. 3013-3020 ◽  
Author(s):  
H Chiba ◽  
J Clifford ◽  
D Metzger ◽  
P Chambon
Keyword(s):  
Retinoic Acid ◽  
Embryonal Carcinoma ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Retinoid X Receptor ◽  
Embryonal Carcinoma Cell ◽  
Retinoid Receptor ◽  
Embryonal Carcinoma Cell Line ◽  
Control Of Expression

The F9 murine embryonal carcinoma cell line represents a well-established system for the study of retinoid signaling in vivo. We have investigated the functional specificity of different retinoid X receptor (RXR)-retinoic acid (RA) receptor (RAR) isotype pairs for the control of expression of endogenous RA-responsive genes, by using wild-type (WT), RXR alpha(-/-), RAR alpha(-/-), RAR gamma(-/-), RXR alpha(-/-)-RAR alpha(-/-), and RXR alpha(-/-)-RAR gamma(-/-) F9 cells, as well as panRXR and RAR isotype (alpha, beta, and gamma)-selective retinoids. We show that in these cells the control of expression of different sets of RA-responsive genes is preferentially mediated by distinct RXR-RAR isotype combinations. Our data support the conclusion that RXR-RAR heterodimers are the functional units transducing the retinoid signal and indicate in addition that these heterodimers exert both specific and redundant functions on the expression of particular sets of RA-responsive genes. We also show that the presence of a given receptor isotype can hinder the activity of another isotype and therefore that functional redundancy between retinoid receptor isotypes can be artifactually generated by gene knockouts.

Evidence that Shh cooperates with a retinoic acid inducible co-factor to establish ZPA-like activity

Development ◽  
1996 ◽  
Vol 122 (2) ◽  
pp. 537-542 ◽  
Author(s):  
T. Ogura ◽  
I.S. Alvarez ◽  
A. Vogel ◽  
C. Rodriguez ◽  
R.M. Evans ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Sonic Hedgehog ◽  
Embryonal Carcinoma ◽  
Carcinoma Cell ◽  
Retinoic Acid Receptor ◽  
Mirror Image ◽  
Limb Bud ◽  
Embryonal Carcinoma Cell ◽  
Embryonal Carcinoma Cell Line ◽  
Vertebrate Limb

Patterning across the anteroposterior axis of the vertebrate limb bud involves a signal from the polarizing region, a small group of cells at the posterior margin of the bud. Retinoic acid (RA; Tickle, C., Alberts, B., Wolpert, L. and Lee, J. (1982) Nature 296, 554–566) and Sonic hedgehog (Shh; Riddle, R. D. Johnson, R. L., Laufer, E. and Tabin, C. J. (1993) Cell 25, 1401–1416; Chang, D. T., Lopez, A., von Kessler, D. P., Chiang, C., Simandl, B. K., Zhao, R., Seldin, M. F., Fallon, J. F. and Beachy, P. A. (1994 Development 120, 3339–3353) have been independently postulated as such signals because they can mimic the mirror image digit duplication obtained after grafting polarizing cells to the anterior of limb buds. Here we show that a embryonal carcinoma cell line, P19, transfected with a Shh expression vector shows low polarizing activity, but when cultured with retinoic acid, duplications like those induced by the polarizing region (ZPA) arise. Complete duplications are also obtained by cotransfecting P19 Shh cells with a constitutively active human retinoic acid receptor (VP16-hRARalpha). These data suggest that Shh and RA cooperate in generating ZPA activity and that Shh, while essential, may not act alone in this process.

scholarly journals 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.

1995 ◽  
Vol 15 (12) ◽  
pp. 6481-6487 ◽  
Author(s):  
B Roy ◽  
R Taneja ◽  
P Chambon
Keyword(s):  
Retinoic Acid ◽  
Cell Differentiation ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Significant Degree ◽  
Retinoid X Receptor ◽  
Embryonal Carcinoma Cell ◽  
Synergistic Activation ◽  
Selective Ligand

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.

scholarly journals Specific and Redundant Functions of Retinoid X Receptor/Retinoic Acid Receptor Heterodimers in Differentiation, Proliferation, and Apoptosis of F9 Embryonal Carcinoma Cells

1997 ◽  
Vol 139 (3) ◽  
pp. 735-747 ◽  
Author(s):  
Hideki Chiba ◽  
John Clifford ◽  
Daniel Metzger ◽  
Pierre Chambon
Keyword(s):  
Retinoic Acid ◽  
Embryonal Carcinoma ◽  
Retinoic Acid Receptor ◽  
Retinoid X Receptor ◽  
Carcinoma Cells ◽  
Embryonal Carcinoma Cells ◽  
Acid Receptor ◽  
Proliferation And Apoptosis ◽  
Redundant Functions

We have generated F9 murine embryonal carcinoma cells in which either the retinoid X receptor (RXR)α and retinoic acid receptor (RAR)α genes or the RXRα and RARγ genes are knocked out, and compared their phenotypes with those of wild-type (WT), RXRα−/−, RARα−/−, and RARγ−/− cells. RXRα−/−/ RARα−/− cells were resistant to retinoic acid treatment for the induction of primitive and parietal endodermal differentiation, as well as for antiproliferative and apoptotic responses, whereas they could differentiate into visceral endodermlike cells, as previously observed for RXRα−/− cells. In contrast, RXRα−/−/RARγ−/− cells were defective for all three types of differentiation, as well as antiproliferative and apoptotic responses, indicating that RXRα and RARγ represent an essential receptor pair for these responses. Taken together with results obtained by treatment of WT and mutant F9 cells with RAR isotype– and panRXR-selective retinoids, our observations support the conclusion that RXR/ RAR heterodimers are the functional units mediating the retinoid signal in vivo. Our results also indicate that the various heterodimers can exert both specific and redundant functions in differentiation, proliferation, and apoptosis. We also show that the functional redundancy exhibited between RXR isotypes and between RAR isotypes in cellular processes can be artifactually generated by gene knockouts. The present approach for multiple gene targeting should allow inactivation of any set of genes in a given cell.

Ligand-inducible retinoid X receptor-mediated protein: DNA interactions in the retinoic acid receptor β2 gene promoter in vivo

1998 ◽  
Vol 136 (2) ◽  
pp. 109-118 ◽  
Author(s):  
Masato Ikeda ◽  
Remco A Spanjaard ◽  
Elizabeth W Noordhoek ◽  
Akio Kawaguchi ◽  
Toshimasa Onaya ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Gene Promoter ◽  
Retinoid X Receptor ◽  
Dna Interactions ◽  
Acid Receptor ◽  
Protein Dna Interactions ◽  
Retinoic Acid Receptor Β2

scholarly journals States of developmental commitment of a mouse embryonal carcinoma cell line differentiating along a neural pathway.

1989 ◽  
Vol 109 (5) ◽  
pp. 2481-2493 ◽  
Author(s):  
E Lang ◽  
M L Mazauric-Stüker ◽  
A Maelicke
Keyword(s):  
Retinoic Acid ◽  
Cell Line ◽  
Embryonal Carcinoma ◽  
Carcinoma Cell ◽  
Neuronal Cell ◽  
Carcinoma Cell Line ◽  
Mammalian Brain ◽  
Embryonal Carcinoma Cell ◽  
Induced Differentiation ◽  
Embryonal Carcinoma Cell Line

The embryonal carcinoma cell line PCC7-S-AzaR1 (clone 1009) has been shown to differentiate in the presence of all-trans retinoic acid and dibutyryl cAMP into cells of predominantly neural properties (Paulin, D., H. Jakob, F. Jacob, K. Weber, and M. Osborn. 1982. Differentiation. 22:90-99). By analyzing the marker expression of derivatives in further detail, we characterized the two major cell phenotypes as neuron- and fibroblast-like and the two minor ones as astroglia- and endothelial-like. The stability of developmental commitment of clone 1009 was tested by recloning. The isolated subclones exhibited different patterns of chemically induced derivatives, with some of them (denoted N-clones) producing only a single (neuronal) cell type. As shown by long-term cultures in the absence of retinoic acid, the properties of isolated subclones remained essentially stable. In contrast to the clones producing neuron-like and other derivatives upon induced differentiation, the (exclusively neuronal) derivatives of N-clones detached and died within a few days in culture. If maintained in the presence of other neural cell types, however, their survival was dramatically extended indicating a requirement for specific interactions with other cells of the same tissue. The patterns of derivatives obtained from N-clones depended on the chemical nature of the substrate on which they were grown. Thus, when seeded on laminin-coated surfaces before induced differentiation, N-clones developed not only to neuron-like derivatives but rather to the same four derivatives observed with the original cell pool. These and further results suggest a common cell lineage of the identified phenotypes. The isolated subclones of uninduced cells probably represent different states of commitment within the same developmental pathway. Their stability offers the opportunity to analyze the nature of cellular commitment on the cellular, molecular, and genetic levels. This makes the family of clones derived from PCC7-S-AzaR1 (clone 1009) cells an advantageous in vitro model of mammalian brain early ontogenesis.

scholarly journals All-trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating both Peroxisome Proliferation-Activated Receptor β/δ and Retinoic Acid Receptor

2009 ◽  
Vol 29 (12) ◽  
pp. 3286-3296 ◽  
Author(s):  
Daniel C. Berry ◽  
Noa Noy
Keyword(s):  
Insulin Resistance ◽  
Retinoic Acid ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Biological Activities ◽  
In Vivo Studies ◽  
Peroxisome Proliferation ◽  
The Metabolic Syndrome ◽  
All Trans Retinoic Acid

ABSTRACT Many biological activities of all-trans-retinoic acid (RA) are mediated by the ligand-activated transcription factors termed retinoic acid receptors (RARs), but this hormone can also activate the nuclear receptor peroxisome proliferation-activated receptor β/δ (PPARβ/δ). We show here that adipocyte differentiation is accompanied by a shift in RA signaling which, in mature adipocytes, allows RA to activate both RARs and PPARβ/δ, thereby enhancing lipolysis and depleting lipid stores. In vivo studies using a dietary-induced mouse model of obesity indicated that onset of obesity is accompanied by downregulation of adipose PPARβ/δ expression and activity. RA treatment of obese mice induced expression of PPARβ/δ and RAR target genes involved in regulation of lipid homeostasis, leading to weight loss and improved insulin responsiveness. RA treatment also restored adipose PPARβ/δ expression. The data indicate that suppression of obesity and insulin resistance by RA is largely mediated by PPARβ/δ and is further enhanced by activation of RARs. By targeting two nuclear receptors, RA may be a uniquely efficacious agent in the therapy and prevention of the metabolic syndrome.

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