Expression of the labial group Hox gene HrHox-1 and its alteration induced by retinoic acid in development of the ascidian Halocynthia roretzi

Development ◽  
1995 ◽  
Vol 121 (10) ◽  
pp. 3197-3205 ◽  
Author(s):  
Y. Katsuyama ◽  
S. Wada ◽  
S. Yasugi ◽  
H. Saiga
Keyword(s):  
Retinoic Acid ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Vertebrate Development ◽  
Halocynthia Roretzi ◽  
Regulation Of Expression ◽  
Hox Gene ◽  
Spatial Regulation ◽  
All Trans Retinoic Acid ◽  
Developmental Features

Ascidian embryogenesis shares several developmental features with vertebrates. Thus, it is presumed that some molecular mechanisms that are critical for vertebrate development may also act in the early development of ascidians. Here, we investigated expression of the ascidian labial group Hox gene HrHox-1 in the development of Halocynthia roretzi. HrHox-1 showed a spatially restricted expression pattern along the anterior-posterior axis, which is remarkably similar to that of the vertebrate gene, Hoxb-1. The expression of HrHox-1, however, was exclusively in tissues of ectoderm origin unlike its vertebrate counterpart. Exposure of the embryos to 10(−6) M all-trans retinoic acid induced a larval phenotype with elimination of the anteriormost structures, the papillae. In this phenotype, the level of HrHox-1 expression was enhanced and ectopic expression was observed at the anterior terminal epidermis where the papillae are otherwise formed. These observations suggest that there are some conserved mechanisms in the spatial regulation of expression of labial group genes in embryogenesis of ascidians and vertebrates.

Developmental role of endogenous retinoids in the determination of morphallactic field in budding tunicates

Development ◽  
1993 ◽  
Vol 117 (3) ◽  
pp. 835-845 ◽  
Author(s):  
K. Kawamura ◽  
K. Hara ◽  
S. Fujiwara
Keyword(s):  
Retinoic Acid ◽  
Aldehyde Dehydrogenase ◽  
Ectopic Expression ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Proximal Extremity ◽  
Developmental Role

We have extracted retinoids from the budding tunicate Polyandrocarpa misakiensis and, using HPLC, identified some major peaks as cis-retinal, all-trans-retinal and all-trans-retinoic acid, of which cis-retinal was most abundant (~2 micromolar). In developing buds, the amount of cis-retinal was about one-fifth that of the adult animals. In those buds, aldehyde dehydrogenase, which could metabolize retinal in vitro, was expressed in epithelial cells and then in mesenchymal cells at the proximal extremity, that is, the future developmental field of the bud. Exogenous retinoic acid comparable to the endogenous level could induce an additional field at the distal end of the bud, resulting in a double monster. The induction always accompanied an ectopic expression of aldehyde dehydrogenase. The results of this work suggest that retinoic acid or related molecule(s) act as an endogenous trigger of morphallactic development of Polyandrocarpa buds.

scholarly journals From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6425-6437 ◽  
Author(s):  
Sai-Juan Chen ◽  
Guang-Biao Zhou ◽  
Xiao-Wei Zhang ◽  
Jian-Hua Mao ◽  
Hugues de Thé ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Promyelocytic Leukemia ◽  
Magic Bullet ◽  
Therapeutic Effects ◽  
New Paradigm ◽  
Therapeutic Benefits ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Arsenic had been used in treating malignancies from the 18th to mid-20th century. In the past 3 decades, arsenic was revived and shown to be able to induce complete remission and to achieve, when combined with all-trans retinoic acid and chemotherapy, a 5-year overall survival of 90% in patients with acute promyelocytic leukemia driven by the t(15;17) translocation-generated promyelocytic leukemia–retinoic acid receptor α (PML-RARα) fusion. Molecularly, arsenic binds thiol residues and induces the formation of reactive oxygen species, thus affecting numerous signaling pathways. Interestingly, arsenic directly binds the C3HC4 zinc finger motif in the RBCC domain of PML and PML-RARα, induces their homodimerization and multimerization, and enhances their interaction with the SUMO E2 conjugase Ubc9, facilitating subsequent sumoylation/ubiquitination and proteasomal degradation. Arsenic-caused intermolecular disulfide formation in PML also contributes to PML-multimerization. All-trans retinoic acid, which targets PML-RARα for degradation through its RARα moiety, synergizes with arsenic in eliminating leukemia-initiating cells. Arsenic perturbs a number of proteins involved in other hematologic malignancies, including chronic myeloid leukemia and adult T-cell leukemia/lymphoma, whereby it may bring new therapeutic benefits. The successful revival of arsenic in acute promyelocytic leukemia, together with modern mechanistic studies, has thus allowed a new paradigm to emerge in translational medicine.

Regulation of c-ret expression by retinoic acid in rat metanephros: implication in nephron mass control

1998 ◽  
Vol 275 (6) ◽  
pp. F938-F945 ◽  
Author(s):  
Evelyne Moreau ◽  
José Vilar ◽  
Martine Lelièvre-Pégorier ◽  
Claudie Merlet-Bénichou ◽  
Thierry Gilbert
Keyword(s):  
Retinoic Acid ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Mrna Level ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
All Trans Retinoic Acid ◽  
Surface Receptor ◽  
Dose Dependent

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.

scholarly journals All-trans-retinoic acid-mediated cytoprotection in LLC-PK1 renal epithelial cells is coupled to p-ERK activation in a ROS-independent manner

2017 ◽  
Vol 313 (6) ◽  
pp. F1200-F1208 ◽  
Author(s):  
Jessica M. Sapiro ◽  
Terrence J. Monks ◽  
Serrine S. Lau
Keyword(s):  
Cell Death ◽  
Retinoic Acid ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Independent Manner ◽  
Toxicant Exposure ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Survival Pathways

Although all- trans-retinoic acid (ATRA) provides protection against a variety of conditions in vivo, particularly ischemia, the molecular mechanisms underpinning these effects remain unclear. The present studies were designed to assess potential mechanisms by which ATRA affords cytoprotection against renal toxicants in LLC-PK1 cells. Pretreatment of LLC-PK1 cells with ATRA (25 μM) for 24 h afforded cytoprotection against oncotic cell death induced by p-aminophenol (PAP), 2-(glutathion- S-yl)hydroquinone (MGHQ), and iodoacetamide but not against apoptotic cell death induced by cisplatin. Inhibition of protein synthesis with cycloheximide blunted ATRA protection, indicating essential cell survival pathways must be engaged before toxicant exposure to provide cytoprotection. Interestingly, ATRA did not prevent the PAP-induced generation of reactive oxygen species (ROS) nor did it alter glutathione levels. Moreover, ATRA had no significant effect on Nrf2 protein expression, and the Nrf2 inducers sulforaphane and MG132 did not influence ATRA cytoprotection, suggesting cytoprotective pathways beyond those that influence ROS levels contribute to ATRA protection. In contrast, ATRA rapidly (15 min) induced levels of the cellular stress kinases p-ERK and p-AKT at concentrations of ATRA (10 and 25 μM) required for cytoprotection. Consistent with a role for p-ERK in ATRA-mediated cytoprotection, inhibition of p-ERK with PD98059 reduced the ability of ATRA to afford protection against PAP toxicity. Collectively, these data suggest that p-ERK and its downstream targets, independent of ROS and antioxidant signaling, are important contributors to the cytoprotective effects of ATRA against oncotic cell death.

scholarly journals All-Trans Retinoic Acid Enhances Chemosensitivity to 5-FU by Targeting miR-378c/E2F7 Axis in Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Ji Li ◽  
Qing Xiang ◽  
Mei Wang ◽  
Hongchang Zhang ◽  
Rong Liang
Keyword(s):  
Retinoic Acid ◽  
Molecular Mechanisms ◽  
Vital Role ◽  
Luciferase Reporter ◽  
Inhibitory Effects ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Diphenyltetrazolium Bromide ◽  
Life Threatening ◽  
Hct116 Cells

Colorectal carcinoma (CRC), a life-threatening malignancy, has been found to present resistance to 5-fluorouracil (5-FU) and cause a poor prognosis for patients. Previous studies have proved that all-trans retinoic acid (ATRA) could inhibit the development of CRC cells. In addition, miR-378c was discovered to exert a vital role in various cancers. In this study, we utilized MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), transwell assay, and flow cytometry to confirm that ATRA was able to enhance the inhibitory effects of 5-FU on HCT116 cells effectively by promoting cell apoptosis. Then, ENCORI database (http://starbase.sysu.edu.cn/) was employed to predict that miR-378c was downregulated dramatically in CRC and E2F7 was the direct target of miR-378c. QRT-PCR (quantitative real-time polymerase chain reaction) was conducted to verify that the expression level of miR-378c was decreased while E2F7 expression was upregulated in CRC tissues compared with para-carcinoma tissues. Additionally, treatment of 5-FU combined with ATRA could increase miR-378c expression, whereas it decreased the expression of E2F7. Dual-Luciferase Reporter assay results revealed that miR-378c could regulate the load of E2F7 by binding to its 3′UTR directly. Furthermore, miR-378c inhibitor or vector with E2F7 partially counteracted the effects of 5-FU combined with ATRA on viability, migration, invasion, and apoptosis of HCT116 cells. In conclusion, our study aims to confirm that ATRA enhances chemosensitivity to 5-FU of patients with CRC and expound the potential molecular mechanisms.

Defective lens fiber differentiation and pancreatic tumorigenesis caused by ectopic expression of the cellular retinoic acid-binding protein I

Development ◽  
1993 ◽  
Vol 119 (2) ◽  
pp. 363-375
Author(s):  
A.V. Perez-Castro ◽  
V.T. Tran ◽  
M.C. Nguyen-Huu
Keyword(s):  
Retinoic Acid ◽  
Binding Proteins ◽  
Binding Protein ◽  
Ectopic Expression ◽  
Retinoic Acid Receptors ◽  
Acid Binding Protein ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Retinoic Acid Binding Proteins

All-trans retinoic acid, a metabolite of retinol, is a possible morphogen in vertebrate development. Two classes of cellular proteins, which specifically bind all-trans retinoic acid, are thought to mediate its action: the nuclear retinoic acid receptors (RAR alpha, beta, gamma), and the cytoplasmic binding proteins known as cellular retinoic acid-binding proteins I and II (CRABP I and II). The function of the retinoic acid receptors is to regulate gene transcription by binding to DNA in conjunction with the nuclear retinoid X receptors (RXR alpha, beta, gamma), which in turn have 9-cis retinoic acid as a ligand. Several lines of evidence suggest that the role of the cellular retinoic acid-binding proteins is to control the concentration of free retinoic acid reaching the nucleus in a given cell. Here, we have addressed the role of the cellular retinoic acid-binding protein I in development by ectopically expressing it in the mouse lens, under the control of the alpha A-crystallin promoter. We show that this ectopic expression interferes with the development of the lens and with the differentiation of the secondary lens fiber cells, causing cataract formation. These results suggest that correct regulation of intracellular retinoic acid concentration is required for normal eye development. In addition, the generated transgenic mice also present expression of the transgene in the pancreas and develop pancreatic carcinomas, suggesting that overexpression of the cellular retinoic acid-binding protein is the cause of the tumors. These results taken together provide evidence for a role of the cellular retinoic acid-binding protein in development and cell differentiation. The relevance of these findings to the possible role of the cellular retinoic acid-binding proteins in the transduction of the retinoic acid signal is discussed.

Proteome Analysis of Apoptotic MR2 Cells, Acute Promyelocytic Leukemia Cell Line with All-Trans Retinoic Acid Resistance, Induced by Arsenic Trioxide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4726-4726
Author(s):  
Pengcheng He ◽  
Mei Zhang ◽  
Xiaoning Wang ◽  
Huaiyu Wang ◽  
Jieying Xi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Cell Line ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Promyelocytic Leukemia ◽  
Beta Tubulin ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Although all-trans retinoic acid(ATRA) provides complete remission in 90% patients with untreated acute promyelocytic leukemia(APL), it becomes ineffective to quite a few APL patients who have received ATRA before when their disease relapsed and used ATRA again. Arsenic trioxide(ATO) can make APL patients with ATRA-resistance obtain complete remission again by inducing APL cells apoptosis. However, the molecular mechanisms of apoptosis in ATRA-resistance APL cells induced by ATO remain unclear. For this reason, we take the apoptotic MR2 cells (APL cell line with ATRA-resistance) induced by ATO as a model, to screen and identify the proteins related with ATO-induced apoptosis by comparative proteomics. After MR2 cells were dyed with annexin V and PI staining, the percentage of the apoptotic MR2 cells induced by 1.0μmol/L ATO for 0h, 6h, 12h, 24h and 48h respectively was detected by Flow cytometry. The results showed that the majority of the apoptotic cells were in the earlier and later stage of apoptosis respectively, when MR2 cells were treated with ATO for 24 and 48 hours in sequence. The total proteins of MR2 cells of the control group, the earlier stages apoptosis group and the later stages apoptosis group were separated by two-dimensional electrophoresis(2-DE) respectively. Then, the differences in proteome profile among three groups were analyzed by ImageMaster™ 2D Platinum software. 14 protein pots were selected to be identified by Matrix-assisted laser desorption/ionization time of flight-mass spectrometry(MALDI-TOF-MS), in which the quantity of the protein differentially expressed was more than two times(≥2 or ≤0.5) among MR2-0h, MR2-24h and MR2-48h cells’ 2-DE map. However, only 11 proteins were successfully identified and their definite information was obtained. Among them, there were 8 proteins that were all probably involved in the mechanisms of apoptosis in MR2 cells and they were Calreticulin(CRT), Heat shock 70 kDa protein(HSP70), High mobility group protein B1(HMGB1), Ran-specific GTPase-activating protein(RanGAP1), Elongation factor 1-beta(EF-1β), Beta-tubulin, Cofilin-1, and Prolyl 4-hydroxylase(P4H) respectively. CRT was probably related with the early stage of apoptosis in MR2 cells, while RanGAP1 and HSP70 might related with the late stage of apoptosis in MR2 cells. Moreover, so far there was no related report on the roles of CRT, HMGB1, RanGAP1, cofilin-1 and beta-tubulin in the mechanisms of APL cells apoptosis. These differential proteins identified provide the new clues for further researching the molecular mechanisms of apoptosis in the ATRA-resistance APL cells induced by ATO.

scholarly journals Bhlhe40/Sirt1 Axis-Regulated Mitophagy Is Implicated in All-Trans Retinoic Acid-Induced Spina Bifida Aperta

2021 ◽  
Vol 9 ◽  
Author(s):  
Lu Zhao ◽  
Dan Liu ◽  
Wei Ma ◽  
Hui Gu ◽  
Xiaowei Wei ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Spina Bifida ◽  
Neural Tube ◽  
Molecular Mechanisms ◽  
Underlying Mechanism ◽  
Neural Tube Closure ◽  
Luciferase Reporter ◽  
All Trans Retinoic Acid ◽  
Spina Bifida Aperta ◽  
First Time

Neural tube defects (NTDs) are the most severe congenital malformations that result from failure of neural tube closure during early embryonic development, and the underlying molecular mechanisms remain elusive. Mitophagy is the best-known way of mitochondrial quality control. However, the role and regulation of mitophagy in NTDs have not yet been elucidated. In this study, we used an all-trans retinoic acid (ATRA)-induced rat model to investigate mitophagy and its underlying mechanism in spina bifida aperta (SBA). The results of western blot, immunofluorescence and RT-qPCR analyses indicated that mitophagy was impaired and Sirt1 was downregulated in SBA. Administration of resveratrol-a strong specific Sirt1 activator-activated Sirt1, thus attenuating autophagy suppression and ameliorating SBA. RNA-sequencing and bioinformatics analysis results indicated that transcriptional regulation played an important role in NTDs. A luciferase reporter assay was performed to demonstrate that the transcription factor Bhlhe40 directly bound to and negatively regulated Sirt1 expression. Further, we discovered that the Bhlhe40/Sirt1 axis regulated mitophagy in neural stem cells. Collectively, our results for the first time demonstrate that Bhlhe40/Sirt1 axis regulated mitophagy is implicated in ATRA-induced SBA. Our findings provide new insights into pathogenesis of NTDs and a basis for potential therapeutic targets for NTDs.

Comparative proteomic analysis of all-trans-retinoic acid treatment reveals systematic posttranscriptional control mechanisms in acute promyelocytic leukemia

Blood ◽  
2004 ◽  
Vol 104 (5) ◽  
pp. 1314-1323 ◽  
Author(s):  
Michael N. Harris ◽  
Bulent Ozpolat ◽  
Fadi Abdi ◽  
Sheng Gu ◽  
Allison Legler ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Growth Inhibition ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Promyelocytic Leukemia ◽  
Initiation Factor ◽  
Control Mechanisms ◽  
Down Regulation ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract All-trans-retinoic acid (ATRA) induces growth inhibition, differentiation, and apoptosis in cancer cells, including acute promyelocytic leukemia (APL). In APL, expression of promyelocytic leukemia protein retinoic acid receptor–α (PML-RARα) fusion protein, owing to the t(15; 17) reciprocal translocation, leads to a block in the promyelocytic stage of differentiation. Here, we studied molecular mechanisms involved in ATRA-induced growth inhibition and myeloid cell differentiation in APL. By employing comprehensive high-throughput proteomic methods of 2-dimensional (2-D) gel electrophoresis and amino acid–coded mass tagging coupled with electrospray ionization (ESI) mass spectrometry, we systematically identified a total of 59 differentially expressed proteins that were consistently modulated in response to ATRA treatment. The data revealed significant down-regulation of eukaryotic initiation and elongation factors, initiation factor 2 (IF2), eukaryotic initiation factor 4AI (eIF4AI), eIF4G, eIF5, eIF6, eukaryotic elongation factor 1A-1 (eEF1A-1), EF-1-δ, eEF1γ, 14-3-3ϵ, and 14-3-3ζ/δ (P < .05). The translational inhibitor DAP5/p97/NAT1 (death-associated protein 5) and PML isoform-1 were found to be up-regulated (P < .05). Additionally, the down-regulation of heterogeneous nuclear ribonucleoproteins (hnRNPs) C1/C2, UP2, K, and F; small nuclear RNPs (snRNPs) D3 and E; nucleoprotein tumor potentiating region (TPR); and protein phosphatase 2A (PP2A) were found (P < .05); these were found to function in pre-mRNA processing, splicing, and export events. Importantly, these proteomic findings were validated by Western blot analysis. Our data in comparison with previous cDNA microarray studies and our reverse transcription–polymerase chain reaction (RT-PCR) experiments demonstrate that broad networks of posttranscriptional suppressive pathways are activated during ATRA-induced growth inhibition processes in APL.

Ectopic expression of Hoxa-1 in the zebrafish alters the fate of the mandibular arch neural crest and phenocopies a retinoic acid-induced phenotype

Development ◽  
1996 ◽  
Vol 122 (3) ◽  
pp. 735-746 ◽  
Author(s):  
D. Alexandre ◽  
J.D. Clarke ◽  
E. Oxtoby ◽  
Y.L. Yan ◽  
T. Jowett ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Neural Crest ◽  
Ectopic Expression ◽  
Head Region ◽  
Hox Gene ◽  
Abnormal Growth ◽  
Primary Body ◽  
Arch Neural ◽  
The Relationship

Considerable evidence has demonstrated that retinoic acid influences the formation of the primary body axis in vertebrates and that this may occur through the regulation of Hox gene expression. In this study, we show that the phenotype induced by exogenous retinoic acid in the zebrafish can also be generated by the overexpression of Hoxa-1 following injection of synthetic RNA into the fertilised egg. The isolation, sequence and expression pattern of the zebrafish Hoxa-1 gene is described. We show that exogenously applied retinoic acid causes the ectopic accumulation of Hoxa-1 message during gastrulation in the hypoblast in the head region. Overexpression of Hoxa-1 following injection of RNA causes abnormal growth of the anterior hindbrain, duplication of Mauthner neurons in rhombomere (r) 2 and fate changes of r2 mesenchymal and neurogenic neural crest. These results are discussed in terms of the role of Hoxa-1 in controlling anterior hindbrain patterning and the relationship between expression of Hoxa-1 and retinoic acid.

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