scholarly journals 9-cis-retinoic acid is a natural antagonist for the retinoic acid receptor response pathway

1993 ◽  
Vol 295 (2) ◽  
pp. 343-346 ◽  
Author(s):  
C Carlberg ◽  
J H Saurat ◽  
G Siegenthaler

The pleiotropic activities of retinoids are mediated by two types of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). All-trans-retinoic acid (RA) transcriptionally activates RARs, but not RXRs, whereas its natural stereoisomer, 9-cis-RA, is the ligand for RXRs. Here, we demonstrate that 9-cis-RA did not transcriptionally activate RARs, whereas in the presence of all-trans-RA the transactivation of RARs was inhibited in a dose-dependent manner by 9-cis-RA. RAR homodimer complexes were destabilized in vitro in the presence of 9-cis-RA. This suggests that 9-cis-RA may be a natural antagonist of all-trans-RA for binding to RAR complexes. The levels of 9-cis-RA may determine by which pathway the transcription of retinoid-responsive genes is modulated.

1998 ◽  
Vol 275 (6) ◽  
pp. F938-F945 ◽  
Author(s):  
Evelyne Moreau ◽  
José Vilar ◽  
Martine Lelièvre-Pégorier ◽  
Claudie Merlet-Bénichou ◽  
Thierry Gilbert

Vitamin A and its derivatives have been shown to promote kidney development in vitro in a dose-dependent fashion. To address the molecular mechanisms by which all- trans-retinoic acid (RA) may regulate the nephron mass, rat kidneys were removed on embryonic day 14( E14) and grown in organ culture under standard or RA-stimulated conditions. By using RT-PCR, we studied the expression of the glial cell line-derived neurotrophic factor (GDNF), its cell surface receptor-α (GDNFR-α), and the receptor tyrosine kinase c-ret, known to play a major role in renal organogenesis. Expression of GDNF and GDNFR-α transcripts was high at the time of explantation and remained unaffected in culture with or without RA. In contrast, c-ret mRNA level, which was low in E14 metanephros and dropped rapidly in vitro, was increased by RA in a dose-dependent manner. The same is true at the protein level. Exogenous GDNF barely promotes additional nephron formation in vitro. Thus the present data establish c-ret as a key target of retinoids during kidney organogenesis.


2014 ◽  
Vol 133 (3) ◽  
pp. 279-286 ◽  
Author(s):  
Lili Xiang ◽  
Rong Wang ◽  
Jiang Wei ◽  
Guoqiang Qiu ◽  
Jiannong Cen ◽  
...  

Background: This study was conducted to determine the antineoplastic activities of 5-aza-2′-deoxycytidine (decitabine; DAC) and all-trans retinoic acid (ATRA), administered either alone or in combination, on in vitro cultured SHI-1 cells as well as their effects on the expression of the tumor suppressor gene p16INK4a (p16) and the retinoic acid receptor (RAR)-β. Methods: Cell growth inhibition, differentiation and apoptosis were determined in SHI-1 cells treated with DAC and/or ATRA, and the combination index of the two compounds was calculated. Methylation of the p16 and RAR-β genes in SHI-1 cells was detected by methylation-specific polymerase chain reaction (PCR). Real-time quantitative reverse transcriptase PCR was used to detect mRNA expression of the p16 and RAR-β genes, and Western blot analysis was performed for protein expression. Results: The drug combination had a synergistic effect on growth inhibition, differentiation and apoptosis of SHI-1 cells, and the effects of DAC and ATRA were dependent on time. DAC, either alone or in combination with ATRA, induced demethylation of the genes p16 and RAR-β, whereas ATRA alone had no effect on methylation. The RAR-β gene was reexpressed following DAC-ATRA combination treatment, and both agents had no effect on p16 expression. Conclusion: The results revealed that DAC used in combination with ATRA has significant clinical potential in the treatment of acute monocytic leukemia. © 2014 S. Karger AG, Basel


Blood ◽  
2010 ◽  
Vol 115 (22) ◽  
pp. 4507-4516 ◽  
Author(s):  
Shuchi Agrawal-Singh ◽  
Steffen Koschmieder ◽  
Sandra Gelsing ◽  
Carol Stocking ◽  
Martin Stehling ◽  
...  

Abstract Although the potential role of Pim2 as a cooperative oncogene has been well described in lymphoma, its role in leukemia has remained largely unexplored. Here we show that high expression of Pim2 is observed in patients with acute promyelocytic leukemia (APL). To further characterize the cooperative role of Pim2 with promyelocytic leukemia/retinoic acid receptor α (PML/RARα), we used a well-established PML-RARα (PRα) mouse model. Pim2 coexpression in PRα-positive hematopoietic progenitor cells (HPCs) induces leukemia in recipient mice after a short latency. Pim2-PRα cells were able to repopulate mice in serial transplantations and to induce disease in all recipients. Neither Pim2 nor PRα alone was sufficient to induce leukemia upon transplantation in this model. The disease induced by Pim2 overexpression in PRα cells contained a slightly higher fraction of immature myeloid cells, compared with the previously described APL disease induced by PRα. However, it also clearly resembled an APL-like phenotype and showed signs of differentiation upon all-trans retinoic acid (ATRA) treatment in vitro. These results support the hypothesis that Pim2, which is also a known target of Flt3-ITD (another gene that cooperates with PML-RARα), cooperates with PRα to induce APL-like disease.


1995 ◽  
Vol 15 (7) ◽  
pp. 3540-3551 ◽  
Author(s):  
L Nagy ◽  
V A Thomázy ◽  
G L Shipley ◽  
L Fésüs ◽  
W Lamph ◽  
...  

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.


2018 ◽  
Vol 69 (7) ◽  
pp. 1817-1820
Author(s):  
Decebal Vasincu ◽  
Roxana Irina Iancu ◽  
Ionut Cazan ◽  
Gabriela Stoleriu ◽  
Marcel Costuleanu

The studies we performed targeted the effects of all-trans retinol (vitamin A) and some retinoid derivatives (including tretinoin or all-trans retinoic acid, retinyl propionate, 9-cis retinoic acid, 13-cis retinoic acid), as well as of tazarotenic acid on apoptosis of rat mesenchymal stem cells, cultured after isolation. Tazarotenic acid is considered to be relatively selective and a potent agonist for RARb and RARg and less for RARa. The same time, tazarotenic acid is not binding to RXRs (retinoid X receptors). The relevant analysis of our experimental results demonstrated that 13-cis retinoic acid was the most potent inducer of apoptosis of cultured mesenchymal stem cells of rat origin when compared to other retinoid derivatives, as follows: 13-cis retinoic acid ] 9-cis retinoic acid ] tazarotenic acid ] all-trans retinoic acid ] retinyl propionate ] retinol (or vitamin A). Very interesting and unexpected were the apoptotic effects of 1 �M tazarotenic acid for 24 hours in our experiments, very close to those induced by all-trans retinoic acid (tretinoin). The apoptosis induced by 13-cis retinoic acid, a principal activator of RARb and RARg, and that induced by 9-cis retinoic acid, a major activator of RXRs, suggests different pathways activated by these retinoid derivatives.


2018 ◽  
Vol 108 (4) ◽  
pp. 784-792 ◽  
Author(s):  
Jessica L Cooperstone ◽  
Janet A Novotny ◽  
Ken M Riedl ◽  
Morgan J Cichon ◽  
David M Francis ◽  
...  

Abstract Background Nonvitamin A apocarotenoids occur in foods. Some function as retinoic acid receptor antagonists in vitro, though it is unclear if apocarotenoids are absorbed or accumulate to levels needed to elicit biological function. Objective The aim of this study was to quantify carotenoids and apocarotenoids (β-apo-8′-, -10′-, -12′-, and -14′-carotenal, apo-6′-, -8′-, -10′-, -12′-, and -14′-lycopenal, retinal, acycloretinal, β-apo-13-carotenone, and apo-13-lycopenone) in human plasma after controlled consumption of carotenoid-rich tomato juices. Design Healthy subjects (n = 35) consumed a low-carotenoid diet for 2 wk, then consumed 360 mL of high-β-carotene tomato juice (30.4 mg of β-carotene, 34.5 μg total β-apocarotenoids/d), high-lycopene tomato juice (42.5 mg of lycopene, 119.2 μg total apolycopenoids/d), or a carotenoid-free control (cucumber juice) per day for 4 wk. Plasma was sampled at baseline (after washout) and after 2 and 4 wk, and analyzed for carotenoids and apocarotenoids using high-pressure liquid chromatography (HPLC) and HPLC-tandem mass spectrometry, respectively. The methods used to analyze the apocarotenoids had limits of detection of ∼ 100 pmol/L. Results Apocarotenoids are present in tomato juices at 0.1–0.5% of the parent carotenoids. Plasma lycopene and β-carotene increased (P < 0.001) after consuming high-lycopene and β-carotene tomato juices, respectively, while retinol remained unchanged. β-Apo-13-carotenone was found in the blood of all subjects at every visit, although elevated (P < 0.001) after consuming β-carotene tomato juice for 4 wk (1.01 ± 0.27 nmol/L) compared with both baseline (0.37 ± 0.17 nmol/L) and control (0.46 ± 0.11 nmol/L). Apo-6′-lycopenal was detected or quantifiable in 29 subjects, while β-apo-10′- and 12′-carotenal were detected in 6 and 2 subjects, respectively. No other apolycopenoids or apocarotenoids were detected. Conclusions β-Apo-13-carotenone was the only apocarotenoid that was quantifiable in all subjects, and was elevated in those consuming high-β-carotene tomato juice. Levels were similar to previous reports of all-trans-retinoic acid. Other apocarotenoids are either poorly absorbed or rapidly metabolized or cleared, and so are absent or limited in blood. β-Apo-13-carotenone may form from vitamin A and its presence warrants further investigation. This trial was registered at clinicaltrials.gov as NCT02550483.


1995 ◽  
Vol 14 (1) ◽  
pp. 101-108 ◽  
Author(s):  
Y-J Y Wan ◽  
T Pan ◽  
L Wang ◽  
J Locker ◽  
T-C J Wu

ABSTRACT In McA-RH 8994 rat hepatoma cells, all-transretinoic acid (t-RA) induces expression of the α-fetoprotein (AFP) and albumin genes and results in a phenotype similar to differentiated fetal hepatocytes. The present study elucidated the mechanism involved in AFP gene regulation mediated by retinoic acid. Northern blot analyses demonstrated that 9-cis-retinoic acid (c-RA), a ligand for retinoid x receptors (RXRs), also induced expression of the AFP gene in McA-RH 8994 cells. The induction was time- and dose-dependent. Northern blots and transfection assays using the 7·3 kb full-length regulatory region of the AFP gene demonstrated that c-RA was more effective than t-RA in regulating expression of the AFP gene. At 10−7m, c-RA increased AFP mRNA 5-fold and chloramphenicol acetyltransferase (CAT) activity 2·5-fold. In contrast, t-RA at a concentration of 10−7 m exerted no significant effect; 10− 6 to 10−5 m t-RA was needed to affect AFP gene expression. These data suggested that activation of RXRs is essential for the regulation of the AFP gene. Co-transfection experiments revealed that overexpression of RXRα in McA-RH 8994 cells further enhanced the CAT activity induced by c-RA. In addition, c-RA did not alter the half-life of AFP mRNA. Thus, RXRα may play a crucial role in transcriptional regulation of the AFP gene and in controlling hepatocyte phenotype.


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