scholarly journals Accumulation of Retinoid X Receptor-α in Uterine Leiomyomas Is Associated with a Delayed Ligand-Dependent Proteasome-Mediated Degradation and an Alteration of Its Transcriptional Activity

2007 ◽  
Vol 21 (3) ◽  
pp. 602-612 ◽  
Author(s):  
Debora Lattuada ◽  
Paola Viganó ◽  
Silvia Mangioni ◽  
Jenny Sassone ◽  
Stefania Di Francesco ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Target Genes ◽  
Specific Inhibitor ◽  
Retinoid X Receptor ◽  
Uterine Leiomyomas ◽  
Full Length ◽  
Molecular Alteration ◽  
Ubiquitin Proteasome

Abstract An alteration of the retinoid pathway can influence the development of uterine leiomyomas in animal models, and retinoids have shown efficacy in inhibiting the growth of this benign tumor both in vitro and in vivo. However, the underlying mechanisms and biological implications are unclear. The present study was based on the demonstration of an accumulation of full-length retinoid X receptor α (RXRα) in leiomyomas that was not associated with a modification of its gene expression. This accumulation was shown to increase the transcription of the RXR-responsive gene cellular retinoic acid binding protein II (CRABP-II) and to be linked to the cellular redistribution of the receptor and to its retarded degradation via the ubiquitin/proteasome pathway. Accordingly, treatment with a specific proteasome inhibitor but not with protease inhibitors strongly inhibited the degradation of full-length RXRα in cells deriving from both myometrium and leiomyoma, but the formation of RXRα/ubiquitin conjugates was differentially regulated between the two cell types. Moreover, full-length RXRα accumulated in leiomyomas was abnormally phosphorylated at serine/threonine residues relative to myometrial tissue. The ligand to RXRα, 9-cis-retinoic acid, induced the receptor breakdown in smooth muscle cells deriving from both normal and tumor tissue, whereas a MAPK-specific inhibitor was able to reduce RXRα levels only in leiomyoma cells. These results suggest that switching of the ubiquitin/proteasome-dependent degradation of RXRα by phosphorylation in leiomyomas may be responsible for the accumulation of the receptor and the consequent dysregulation of retinoic acid target genes. The ability of retinoids to modify this molecular alteration may be the rationale for their use in the treatment of leiomyomas.

scholarly journals 9-cis-Retinoic Acid Inhibits Androgen Receptor Activity through Activation of Retinoid X Receptor

2005 ◽  
Vol 19 (5) ◽  
pp. 1200-1212 ◽  
Author(s):  
Kuang-Hsiang Chuang ◽  
Yi-Fen Lee ◽  
Wen-Jye Lin ◽  
Chin-Yi Chu ◽  
Saleh Altuwaijri ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Retinoic Acid ◽  
Androgen Receptor ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Retinoid X Receptor ◽  
Androgen Receptor Activity ◽  
Functional Analyses

Abstract Although the retinoic X receptor (RXR) forms heterodimers with many members of the estrogen receptor subfamily, the interaction between RXR and the members of the glucocorticoid receptor subfamily remains unclear. Here we show that the RXR can form a heterodimer with the androgen receptor (AR) under in vitro and in vivo conditions. Functional analyses further demonstrated that the AR, in the presence or absence of androgen, can function as a repressor to suppress RXR target genes, thereby preventing the RXR binding to the RXR DNA response element. In contrast, RXR can function as a repressor to suppress AR target genes in the presence of 9-cis-retinoic acid, but unliganded RXR can function as a weak coactivator to moderately enhance AR transactivation. Together, these results not only reveal a unique interaction between members of the two nuclear receptor subfamilies, but also represent the first evidence showing a nuclear receptor (RXR) may function as either a repressor or a coactivator based on the ligand binding status.

scholarly journals Physiological and Receptor-selective Retinoids Modulate Interferon γ Signaling by Increasing the Expression, Nuclear Localization, and Functional Activity of Interferon Regulatory Factor-1

2005 ◽  
Vol 280 (43) ◽  
pp. 36228-36236 ◽  
Author(s):  
Xin M. Luo ◽  
A. Catharine Ross
Keyword(s):  
Retinoic Acid ◽  
Nuclear Localization ◽  
Target Genes ◽  
Interferon Γ ◽  
Epithelial Cell Line ◽  
Transcriptional Level ◽  
Signal Transducer ◽  
Regulatory Factor

Synergistic actions between all-trans-retinoic acid (atRA) and interferon γ (IFNγ) on modulation of cellular functions have been reported both in vitro and in vivo. However, the mechanism of atRA-mediated regulation of IFNγ signaling is poorly understood. In this study, we have used the human lung epithelial cell line A549 to examine the effect of atRA on IFNγ-induced expression of IFN regulatory factor-1 (IRF-1), an important transcription factor involved in cell growth and apoptosis, differentiation, and antiviral and antibacterial immune responses. At least 4 h of pretreatment with atRA followed by suboptimal concentrations of IFNγ induced a faster, higher, and more stable expression of IRF-1 than IFNγ alone. Actinomycin D completely blocked the induction of IRF-1 by the combination, suggesting regulation at the transcriptional level. Further, we found that activation of signal transducer and activator of transcription-1 was induced more dramatically by atRA and IFNγ than by IFNγ alone. Expression of IFNγ receptor-1 on the cell surface was also increased upon atRA pretreatment. Experiments using receptor-selective retinoids revealed that ligands for retinoic acid receptor-α (RARα), including atRA, 9-cis-retinoic acid, and Am580, sequentially increased the levels of IFNγ receptor-1, activated signal transducer and activator of transcription-1, and IRF-1 and that an RARα antagonist was able to inhibit the effects of atRA and Am580. In addition, atRA pretreatment affected the transcriptional functions of IFNγ-induced IRF-1, increasing its nuclear localization and DNA binding activity as well as the transcript levels of IRF-1 target genes. These results suggest that atRA, an RARα ligand, regulates IFNγ-induced IRF-1 by affecting multiple components of the IFNγ signaling pathway, from the plasma membrane to the nuclear transcription factors.

scholarly journals A new coactivator complex required for retinoic acid-dependent regulation of embryonic symmetry

2016 ◽  
Author(s):  
Goncalo C. Vilhais-Neto ◽  
Marjorie Fournier ◽  
Jean-Luc Plassat ◽  
Mihaela E. Sardiu ◽  
Anita Saraf ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Rna Polymerase Ii ◽  
Protein Complex ◽  
Target Genes ◽  
Bilateral Symmetry ◽  
Molecular Control ◽  
Mouse Mutants ◽  
Proteomic Approach

Bilateral symmetry is a striking feature of the vertebrate body plan organization. Vertebral precursors, called somites, provide one of the best illustrations of embryonic symmetry. Maintenance of somitogenesis symmetry requires Retinoic acid (RA) and its coactivator Rere/Atrophin2. Here, using a proteomic approach we identify a protein complex, containing Wdr5, Hdac1, Hdac2 and Rere (named WHHERE), which regulates RA signalling and controls embryonic symmetry. We demonstrate that Wdr5, Hdac1 and Hdac2 are required for RA signalling in vitro and in vivo. Mouse mutants for Wdr5 and Hdac1 exhibit asymmetrical somite formation characteristic of RA-deficiency. We also identify the Rere-binding histone methyltransferase Ehmt2/G9a, as a RA coactivator controlling somite symmetry. Upon RA treatment, WHHERE and Ehmt2 become enriched at RA target genes to promote RNA Polymerase II recruitment. Our work identifies a novel protein complex linking key epigenetic regulators acting in the molecular control of embryonic bilateral symmetry.

Retinoic acid action is altered within endometrium of baboons affected with endometriosis

2022 ◽  
pp. 228402652110620
Author(s):  
Mary Ellen Pavone ◽  
Allison R Grover ◽  
Rafael Confino ◽  
Elizabeth K Pearson ◽  
Saurabh Malpani ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Menstrual Cycle ◽  
Disease Progression ◽  
Cell Fate ◽  
Cellular Response ◽  
Target Genes ◽  
Baboon Model ◽  
Disease Induction

Objective: Using a baboon model, we determined the changing expression of Retinoic Acid (RA) target genes during the menstrual cycle and during disease progression. This change could explain the cellular response and changes characteristic of endometriosis. In previous studies, we established that endometriosis affects the CRABP2:FABP5 ratio in an in vitro environment, shifting toward apoptosis and differentiation with higher CRABP2, and anti-apoptosis with higher levels of FABP5. Intervention(s): Endometriosis was induced in female baboons with intraperitoneal inoculation of menstrual endometrium ( n = 2–4). Tissue was harvested via endometrectomy during different stages of the menstrual cycle as well at 3, 6, and 12 month timepoints after inoculation with endometriosis. Main outcome measure(s): Real time PCR was used to quantify STRA6 (a gene responsible for retinol uptake), CRABP2 (a gene necessary for apoptotic and anti-apoptotic estrogenic RA effects), and FABP5 (a gene that mediates the anti-apoptotic actions of RA). Results: STRA6 and CRABP2 expression were highest in the proliferative phase and lowest in the late secretory phase. FABP5 expression remained stable throughout the 12 months following the induction of the disease, whereas STRA6 and CRABP2 continued to decrease during the same period. Conclusions: Our study confirms that a shift in the CRABP2:FABP5 ratio has similar in vivo effects as it does in vitro: changing RA expression with disease induction and progression. As CRABP2 may be important in determining cell fate in the endometrium, gene expression changes could contribute to the anti-apoptotic behavior of affected cells. As expression changes more during progression, earlier rather than later treatment becomes more critical in reducing the rate of disease progression.

scholarly journals MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid

2021 ◽  
Vol 9 ◽  
Author(s):  
Hiroki Yoshioka ◽  
Yurie Mikami ◽  
Sai Shankar Ramakrishnan ◽  
Akiko Suzuki ◽  
Junichi Iwata
Keyword(s):  
Cell Proliferation ◽  
Retinoic Acid ◽  
Cleft Palate ◽  
Cleft Lip ◽  
Specific Inhibitor ◽  
Mouse Embryos ◽  
Congenital Birth Defects ◽  
Excessive Intake

Cleft lip with/without cleft palate (CL/P) is one of the most common congenital birth defects, showing the complexity of both genetic and environmental contributions [e.g., maternal exposure to alcohol, cigarette, and retinoic acid (RA)] in humans. Recent studies suggest that epigenetic factors, including microRNAs (miRs), are altered by various environmental factors. In this study, to investigate whether and how miRs are involved in cleft palate (CP) induced by excessive intake of all-trans RA (atRA), we evaluated top 10 candidate miRs, which were selected through our bioinformatic analyses, in mouse embryonic palatal mesenchymal (MEPM) cells as well as in mouse embryos treated with atRA. Among them, overexpression of miR-27a-3p, miR-27b-3p, and miR-124-3p resulted in the significant reduction of cell proliferation in MEPM cells through the downregulation of CP-associated genes. Notably, we found that excessive atRA upregulated the expression of miR-124-3p, but not of miR-27a-3p and miR-27b-3p, in both in vivo and in vitro. Importantly, treatment with a specific inhibitor for miR-124-3p restored decreased cell proliferation through the normalization of target gene expression in atRA-treated MEPM cells and atRA-exposed mouse embryos, resulting in the rescue of CP in mice. Taken together, our results indicate that atRA causes CP through the induction of miR-124-3p in mice.

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.

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 Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia

2013 ◽  
Vol 210 (13) ◽  
pp. 2793-2802 ◽  
Author(s):  
Guilherme Augusto dos Santos ◽  
Lev Kats ◽  
Pier Paolo Pandolfi
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Pml Nuclear Bodies ◽  
Molecular Events

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by a chimeric oncoprotein containing the C terminus of the retinoic acid receptor-a (RARa) fused to an N-terminal partner, most commonly promyelocytic leukemia protein (PML). Mechanistically, PML-RARa acts as a transcriptional repressor of RARa and non-RARa target genes and antagonizes the formation and function of PML nuclear bodies that regulate numerous signaling pathways. The empirical discoveries that PML-RARa–associated APL is sensitive to both all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), and the subsequent understanding of the mechanisms of action of these drugs, have led to efforts to understand the contribution of molecular events to APL cell differentiation, leukemia-initiating cell (LIC) clearance, and disease eradication in vitro and in vivo. Critically, the mechanistic insights gleaned from these studies have resulted not only in a better understanding of APL itself, but also carry valuable lessons for other malignancies.

scholarly journals Hsp90α Recruited by Sp1 Is Important for Transcription of 12(S)-Lipoxygenase in A431 Cells

2005 ◽  
Vol 280 (43) ◽  
pp. 36283-36292 ◽  
Author(s):  
Jan-Jong Hung ◽  
Chih-Ying Wu ◽  
Pao-Chi Liao ◽  
Wen-Chang Chang
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Target Genes ◽  
Specific Inhibitor ◽  
A431 Cells ◽  
Rich Region ◽  
Immunoprecipitation Assay ◽  
Protein Levels ◽  
In Cells

Sp1 is a basic transcriptional factor that binds to the GC-rich region in the promoter of the target gene. It is involved in transcription of numerous genes by recruiting transcriptional factors to the promoters of target genes. In this study, we found in vivo and in vitro that Hsp90α was recruited to the GC-rich region of the 12(S)-lipoxygenase promoter through interaction with Sp1 in A431 cells by employing DNA affinity immunoprecipitation assay and chromatin immunoprecipitation assay. When Hsp90α was inhibited by geldanamycin (GA, a specific inhibitor of the Hsp90 family) or by siRNA of Hsp90α (to block its activity or to knockdown protein levels), respectively, luciferase activity (driven by the 12(S)-lipoxygenase promoter) and both mRNA and protein levels of 12(S)-lipoxygenase were reduced significantly in cells. In addition, the effect of GA was abolished when the Sp1 binding sites of 12(S)-lipoxygenase were mutated in A431 cells. Interestingly, binding of Sp1 to the 12(S)-lipoxygenase promoter was also decreased upon GA treatment in cells. In conclusion, our results indicate that Sp1 interacts with Hsp90α to recruit it to the promoter of 12(S)-lipoxygenase and then to regulate gene transcription by modulating the binding ability of Sp1 to promoters.

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