scholarly journals Apo-14´-Carotenoic Acid Is a Novel Endogenous and Bioactive Apo-Carotenoid

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2084 ◽  
Author(s):  
Gamze Aydemir ◽  
Marta Domínguez ◽  
Angel R. de Lera ◽  
Johanna Mihaly ◽  
Dániel Törőcsik ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Target Gene ◽  
Retinoic Acid Receptor ◽  
Alternative Pathway ◽  
Gene Activation ◽  
Human Organism ◽  
Retinoic Acids ◽  
Retinoic Acid Response Element ◽  
Reporter Mice ◽  
Β Carotene

Carotenoids can be metabolized to various apo-carotenoids and retinoids. Apo-15´-carotenoic acid (retinoic acid, RA) is a potent activator of the retinoic acid receptor (RAR) in its all-trans- (ATRA) and 9-cis- (9CRA) forms. In this study we show firstly, that apo-14´-carotenoic acid (A14CA), besides retinoic acids, is present endogenously and with increased levels in the human organism after carrot juice supplementation rich in β-carotene. All-trans-A14C (ATA14CA) is just a moderate activator of RAR-transactivation in reporter cell lines but can potently activate retinoic acid response element (RARE)-mediated signalling in DR5/RARE-reporter mice and potently increase retinoid-reporter target gene expression in ATA14CA-supplemented mice and treated MM6 cells. Further metabolism to all-trans-13,14-dihydroretinoic acid (ATDHRA) may be the key for its potent effects on retinoid target gene activation in ATA14CA-treated MM6 cells and in liver of supplemented mice. We conclude that besides RAs, there are alternative ways to activate RAR-response pathways in the mammalian organism. ATA14CA alone and in combination with its metabolite ATDHRA may be an alternative pathway for potent RAR-mediated signalling.

scholarly journals Activation of the phosphoenolpyruvate carboxykinase gene retinoic acid response element is dependent on a retinoic acid receptor/coregulator complex.

1992 ◽  
Vol 12 (12) ◽  
pp. 5527-5535 ◽  
Author(s):  
R K Hall ◽  
D K Scott ◽  
E L Noisin ◽  
P C Lucas ◽  
D K Granner
Keyword(s):  
Retinoic Acid ◽  
Transcriptional Control ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Mutational Analysis ◽  
Retinoic Acid Receptor ◽  
Retinoid Receptor ◽  
Response Element ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Retinoic Acid Response Element

The accessory factor 1 (AF1) element is an upstream transcriptional control region that plays a role in the response of the phosphoenolpyruvate carboxykinase (PEPCK) gene to both glucocorticoids and retinoic acid. We demonstrate here that retinoic acid receptor alpha (RAR alpha) binds to a sequence within the AF1 element, TGACCT (site B), that is a consensus retinoic acid response element (RARE) half-site. A similar DNA sequence, TGGCCG (site C), located 1 bp downstream of site B, is not involved in the binding of RAR alpha monomers or dimers but is required for the constitution of a functional RARE. Site C is also required for the formation of a complex involving RAR alpha and a liver nuclear factor designated CR, for coregulator. Mutational analysis of the AF1 element shows that the RAR alpha/CR complex is the trans-acting unit that mediates the retinoic acid response of the PEPCK gene. Another member of the retinoid receptor family, retinoid X receptor alpha (RXR alpha), can also form a complex with RAR alpha and the AF1 element. Several observations, including the observation that RXR alpha antibody interacts with CR, indicate that RXR alpha and CR are identical or closely related proteins. Through RXR alpha forms a complex with RAR alpha and the AF1 element, we demonstrate that the AF1 element is functionally distinguishable from a retinoid X response element. Taken together, our results show that the AF1 element contains an RARE that mediates a retinoic acid response by binding an RAR alpha/coregulator complex; this coregulator is presumably RXR alpha.

scholarly journals Retinoid receptors cause distortion of the retinoic acid response element in the phosphoenolpyruvate carboxykinase gene promoter

1995 ◽  
Vol 310 (2) ◽  
pp. 483-490 ◽  
Author(s):  
D K Scott ◽  
R K Hall ◽  
D K Granner
Keyword(s):  
Retinoic Acid ◽  
Conformational Changes ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Retinoic Acid Receptor ◽  
Gene Promoter ◽  
Ring Closure ◽  
Retinoid Receptors ◽  
Retinoic Acid Response Element ◽  
Cyclization Kinetics ◽  
Distortion Angle

Functional retinoic acid response elements (RAREs) have been described wherein the direct repeats are separated by 1, 2 or 5 bp (termed DR1, DR2 and DR5 respectively). We have previously shown that retinoic acid receptor/retinoid X receptor (RAR/RXR) binds a DR1 RARE within the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter and is the trans-acting complex that mediates the retinoic acid (RA) response. However, the mechanism of trans-activation is unknown. The consequences of RAR/RXR binding to the PEPCK RARE were examined using a circular permutation analysis as a first step to explore the possible role of DNA conformational changes in the RA response. The RAR/RXR heterodimer produced a distortion angle of 78 degrees. The DNA distortion was shown to be at the centre of the PEPCK RARE; RA did not affect the severity of the distortion angle or the location of the distortion centre. Monomers and homodimers of RAR also distorted the DNA, but to a lesser extent than did RAR/RXR. The results of a phasing analysis demonstrated that RAR/RXR heterodimers did not induce a static DNA bend, in either the presence or the absence of RA. A cyclization kinetics assay was employed to show that RAR/RXR binding affected DNA ring closure in a phase-sensitive, RA-insensitive, manner. Taken together, these observations support the idea that RAR/RXR heterodimers distort the structure of the PEPCK RARE, at least in part, by altering DNA flexibility. The conformational change in the PEPCK RARE upon RAR/RXR binding has implications for how RAR/RXR heterodimers recognize various RARE structures.

scholarly journals Mechanism of Regulation and Suppression of Melanoma Invasiveness by Novel Retinoic Acid Receptor-γ Target Gene Carbohydrate Sulfotransferase 10

2009 ◽  
Vol 69 (12) ◽  
pp. 5218-5225 ◽  
Author(s):  
Xiansi Zhao ◽  
Carole Graves ◽  
Sarah J. Ames ◽  
David E. Fisher ◽  
Remco A. Spanjaard
Keyword(s):  
Retinoic Acid ◽  
Target Gene ◽  
Retinoic Acid Receptor ◽  
Acid Receptor

The t(5;17) acute promyelocytic leukemia fusion protein NPM-RAR interacts with co-repressor and co-activator proteins and exhibits both positive and negative transcriptional properties

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2683-2690 ◽  
Author(s):  
Robert L. Redner ◽  
J. Don Chen ◽  
Elizabeth A. Rush ◽  
Hui Li ◽  
Sheri L. Pollock
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Transcriptional Activation ◽  
Rna Splicing ◽  
Fusion Proteins ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Dominant Negative ◽  
Wild Type ◽  
Retinoic Acid Response Element

The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the genes for nucleophosmin (NPM) and the retinoic acid receptor alpha (RAR). Two NPM-RAR molecules are expressed as a result of alternative RNA splicing. Both contain RAR sequences that encode the DNA binding, heterodimerization, and ligand activation domains of RAR. This study was designed to test the ability of these fusion proteins to act as transcriptional activators of retinoic acid responsive promoters. The NPM-RAR fusion proteins bind to retinoic acid response element sequences as either homodimers or as heterodimers with RXR. Transcription of retinoic acid–inducible promoters is activated by the fusion proteins in the presence of retinoic acid. The level of transactivation induced by the NPM-RAR fusions differs from the level of transactivation induced by wild-type RAR in both a promoter and cell specific fashion, and more closely parallels the pattern of activation of the PML-RAR fusion than wild-type RAR. In addition, NPM-RAR decreases basal transcription from some promoters and acts in a dominant-negative fashion when co-transfected with wild-type RAR. Both NPM-RAR and PML-RAR interact with the co-repressor protein SMRTe in a manner that is less sensitive than RAR to dissociation by retinoic acid. Retinoic acid induces binding of the co-activator protein RAC3. These data indicate that the NPM-RAR fusion proteins can modulate expression of retinoid-responsive genes in a positive or negative manner, depending on context of the promoter, and lend support to the hypothesis that aberrant transcriptional activation underlies the APL phenotype.

scholarly journals GA-Binding Protein and p300 Are Essential Components of a Retinoic Acid-Induced Enhanceosome in Myeloid Cells

2006 ◽  
Vol 26 (8) ◽  
pp. 3060-3070 ◽  
Author(s):  
Karen K. Resendes ◽  
Alan G. Rosmarin
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Binding Protein ◽  
Myeloid Cells ◽  
Dominant Negative ◽  
Proximal Promoter ◽  
Chromosome Conformation ◽  
Retinoic Acid Response Element ◽  
Essential Components ◽  
Ga Binding Protein

ABSTRACT Expression of CD18, the β chain of the leukocyte integrins, is transcriptionally regulated by retinoic acid (RA) in myeloid cells. Full RA responsiveness of the CD18 gene requires its proximal promoter, which lacks a retinoic acid response element (RARE). Rather, RA responsiveness of the CD18 proximal promoter requires ets sites that are bound by GA-binding protein (GABP). The transcriptional coactivator, p300, further increases CD18 RA responsiveness. We demonstrate that GABPα, the ets DNA-binding subunit of GABP, physically interacts with p300 in myeloid cells. This interaction involves the GABPα pointed domain (PNT) and identifies p300 as the first known interaction partner of GABPα PNT. Expression of the PNT domain, alone, disrupts the GABPα-p300 interaction and decreases the RA responsiveness of the CD18 proximal promoter. Chromatin immunoprecipitation and chromosome conformation capture demonstrate that, in the presence of RA, GABPα and p300 at the proximal promoter recruit retinoic acid receptor/retinoid X receptor from a distal RARE to form an enhanceosome. A dominant negative p300 construct disrupts enhanceosome formation and reduces the RA responsiveness of CD18. Thus, proteins on the CD18 proximal promoter recruit the distal RARE in the presence of RA. This is the first description of an RA-induced enhanceosome and demonstrates that GABP and p300 are essential components of CD18 RA responsiveness in myeloid cells.

scholarly journals The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 882-886 ◽  
Author(s):  
RL Redner ◽  
EA Rush ◽  
S Faas ◽  
WA Rudert ◽  
SJ Corey
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Fusion Proteins ◽  
Fusion Gene ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Reading Frame ◽  
Acid Receptor ◽  
Retinoic Acid Response Element

We have studied an acute promyelocytic leukemia (APL) patient with a variant t(5;17)(q32;q12). This translocation fuses the gene for the nucleolar phosphoprotein nucleophosmin (NPM) to the retinoic acid receptor alpha (RARA). Two alternatively spliced transcripts are expressed, which differ in 129 bases immediately upstream of the RARA sequence. The NPM sequences contained in the shorter NPM-RAR cDNA are identical to the NPM sequences contained in the NPM-ALK fusion gene expressed in t(2;5) lymphomas. The RARA sequences are the same as the RARA sequences found in the PML-RAR and PLZF-RAR fusion seen in t(15;17) and t(11;17) APL, respectively. Both NPM-RAR transcripts fuse NPM and RARA sequence in the same reading frame, to generate translation products of 57 kD and 62 kD. Both NPM-RAR proteins are expressed in the patient's leukemic cells, along with wild-type RARA derived from the uninvolved allele. In transcriptional assays using a retinoic acid response element reporter construct, both NPM-RAR fusion proteins act as retinoic acid-dependent transcriptional activators. This case defines a third class of APL rearrangements, all of which generate fusion proteins of RARA.

Pokemon decreases the transcriptional activity of RARα in the absence of ligand

2017 ◽  
Vol 398 (3) ◽  
pp. 331-340 ◽  
Author(s):  
Yutao Yang ◽  
Yueting Li ◽  
Fei Di ◽  
Jiajun Cui ◽  
Yue Wang ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Transcriptional Activity ◽  
Thyroid Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Potential Interaction ◽  
Retinoic Acid Receptor Alpha ◽  
Rare Element ◽  
Retinoic Acid Response Element

Abstract Pokemon is a transcriptional repressor that belongs to the POZ and Krüppel (POK) protein family. In this study, we investigated the potential interaction between Pokemon and retinoic acid receptor alpha (RARα) and determined the role of Pokemon in regulation of RARα transcriptional activity in the absence of ligand. We found that Pokemon could directly interact with RARα. Moreover, we demonstrated that Pokemon could decrease the transcriptional activity of RARα in the absence of ligand. Furthermore, we showed that Pokemon could repress the transcriptional activity of RARα by increasing the recruitment of nuclear receptor co-repressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) to the retinoic acid response element (RARE) element. Taken together, these data suggest that Pokemon is a novel partner of RARα that acts as a co-repressor to regulate RARα transcriptional activity in the absence of ligand.

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