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.

Abstract 356: Krueppel-Like Factor 15 Regulates Wnt/β-Catenin Transcription and Controls Cardiac Progenitor Cell Fate in the Postnatal Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Claudia Noack ◽  
Maria P Zafiriou ◽  
Anke Renger ◽  
Hans J Schaeffer ◽  
Martin W Bergmann ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Activation ◽  
Progenitor Cell ◽  
Cellular Localization ◽  
Target Genes ◽  
Critical Role ◽  
Isolated Cells ◽  
Cardiac Progenitor Cell

Wnt/β-catenin signaling controls adult heart remodeling partly by regulating cardiac progenitor cell (CPC) differentiation. We now identified and characterized a novel cardiac interaction of the transcription factor Krueppel-like factor 15 (KLF15) with the Wnt/β-catenin signaling on adult CPCs. In vitro mutation, reporter gene assays and co-localization studies revealed that KLF15 requires two distinct domains for nuclear localization and for repression of β-catenin-mediated transcription. KLF15 had no effect on β-catenin stability or cellular localization, but interacted with its co-factor TCF4, which is required for activation of β-catenin target gene expression. Moreover, increased TCF4 ubiquitination was induced by KLF15. In line with this finding we found KLF15 to interact with the Nemo-like kinase, which was shown to phosphorylate and target TCF4 for degradation. In vivo analyses of adult Klf15 functional knock-out (KO) vs. wild-type (WT) mice showed a cardiac β-catenin-mediated transcriptional activation and reduced TCF4 degradation along with cardiac dysfunction assessed by echocardiography (n=10). FACS analysis of the CPC enriched-population of KO vs. WT mice revealed a significant reduction of cardiogenic-committed precursors identified as Sca1+/αMHC+ (0.8±0.2% vs. 1.8±0.1%) and Tbx5+ (3.5±0.3% vs. 5.2±0.5%). In contrast, endothelial Sca1+/CD31+ cells were significantly higher in KO mice (11.3±0.4% vs. 8.6±0.4%; n≥9). In addition, Sca1+ isolated cells of Klf15 KO showed increased RNA expression of endothelial markers von Willebrand Factor, CD105, and Flk1 along with upregulation of β-catenin target genes. CPCs co-cultured on adult fibroblasts resulted in increased endothelial Flk1 cells and reduction of αMHC and Hand1 cardiogenic cells in KO vs. WT CPCs (n=9). Treating these co-cultures with Quercetin, an inhibitor of nuclear β-catenin, resulted in partial rescue of the observed phenotype. This study uncovers a critical role of KLF15 for the maintenance of cardiac tissue homeostasis. Via inhibition of β-catenin transcription, KLF15 controls cardiomyogenic cell fate similar to embryonic cardiogenesis. This knowledge may provide a tool for activation of endogenous CPCs in the postnatal heart.

scholarly journals Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity

2020 ◽  
Vol 21 (24) ◽  
pp. 9401
Author(s):  
Antonio Bouthelier ◽  
Florinda Meléndez-Rodríguez ◽  
Andrés A. Urrutia ◽  
Julián Aragonés
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Cellular Response ◽  
Target Gene ◽  
Target Genes ◽  
Transactivation Domain ◽  
Transactivation Domains ◽  
Relative Contribution

Cellular response to hypoxia is controlled by the hypoxia-inducible transcription factors HIF1α and HIF2α. Some genes are preferentially induced by HIF1α or HIF2α, as has been explored in some cell models and for particular sets of genes. Here we have extended this analysis to other HIF-dependent genes using in vitro WT8 renal carcinoma cells and in vivo conditional Vhl-deficient mice models. Moreover, we generated chimeric HIF1/2 transcription factors to study the contribution of the HIF1α and HIF2α DNA binding/heterodimerization and transactivation domains to HIF target specificity. We show that the induction of HIF1α-dependent genes in WT8 cells, such as CAIX (CAR9) and BNIP3, requires both halves of HIF, whereas the HIF2α transactivation domain is more relevant for the induction of HIF2 target genes like the amino acid carrier SLC7A5. The HIF selectivity for some genes in WT8 cells is conserved in Vhl-deficient lung and liver tissue, whereas other genes like Glut1 (Slc2a1) behave distinctly in these tissues. Therefore the relative contribution of the DNA binding/heterodimerization and transactivation domains for HIF target selectivity can be different when comparing HIF1α or HIF2α isoforms, and that HIF target gene specificity is conserved in human and mouse cells for some of the genes analyzed.

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.

scholarly journals Control of skeletal morphogenesis by the Hippo-YAP/TAZ pathway

Development ◽  
2020 ◽  
Vol 147 (21) ◽  
pp. dev187187
Author(s):  
Hannah K. Vanyai ◽  
Fabrice Prin ◽  
Oriane Guillermin ◽  
Bishara Marzook ◽  
Stefan Boeing ◽  
...  
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Control Cell ◽  
Tissue Growth ◽  
Double Knockout ◽  
Cartilage Growth ◽  
Chondrocyte Proliferation ◽  
Specific Expression

ABSTRACTThe Hippo-YAP/TAZ pathway is an important regulator of tissue growth, but can also control cell fate or tissue morphogenesis. Here, we investigate the function of the Hippo pathway during the development of cartilage, which forms the majority of the skeleton. Previously, YAP was proposed to inhibit skeletal size by repressing chondrocyte proliferation and differentiation. We find that, in vitro, Yap/Taz double knockout impairs murine chondrocyte proliferation, whereas constitutively nuclear nls-YAP5SA accelerates proliferation, in line with the canonical role of this pathway in most tissues. However, in vivo, cartilage-specific knockout of Yap/Taz does not prevent chondrocyte proliferation, differentiation or skeletal growth, but rather results in various skeletal deformities including cleft palate. Cartilage-specific expression of nls-YAP5SA or knockout of Lats1/2 do not increase cartilage growth, but instead lead to catastrophic malformations resembling chondrodysplasia or achondrogenesis. Physiological YAP target genes in cartilage include Ctgf, Cyr61 and several matrix remodelling enzymes. Thus, YAP/TAZ activity controls chondrocyte proliferation in vitro, possibly reflecting a regenerative response, but is dispensable for chondrocyte proliferation in vivo, and instead functions to control cartilage morphogenesis via regulation of the extracellular matrix.

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 PRH/Hex: an oligomeric transcription factor and multifunctional regulator of cell fate

2008 ◽  
Vol 412 (3) ◽  
pp. 399-413 ◽  
Author(s):  
Abdenour Soufi ◽  
Padma-Sheela Jayaraman
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Multifunctional Protein ◽  
Select Group ◽  
Cell Proliferation And Differentiation ◽  
Dimerization Interface ◽  
Homeobox Protein ◽  
Specific Mrnas

The PRH (proline-rich homeodomain) [also known as Hex (haematopoietically expressed homeobox)] protein is a critical regulator of vertebrate development. PRH is able to regulate cell proliferation and differentiation and is required for the formation of the vertebrate body axis, the haematopoietic and vascular systems and the formation of many vital organs. PRH is a DNA-binding protein that can repress and activate the transcription of its target genes using multiple mechanisms. In addition, PRH can regulate the nuclear transport of specific mRNAs making PRH a member of a select group of proteins that control gene expression at the transcriptional and translational levels. Recent biophysical analysis of the PRH protein has shown that it forms homo-oligomeric complexes in vivo and in vitro and that the proline-rich region of PRH forms a novel dimerization interface. Here we will review the current literature on PRH and discuss the complex web of interactions centred on this multifunctional protein.

scholarly journals Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence

2021 ◽  
Vol 22 (22) ◽  
pp. 12232
Author(s):  
Nathalie Thorin-Trescases ◽  
Pauline Labbé ◽  
Pauline Mury ◽  
Mélanie Lambert ◽  
Eric Thorin
Keyword(s):  
Cell Fate ◽  
Cellular Senescence ◽  
Cellular Response ◽  
Inflammatory Diseases ◽  
Age Related ◽  
A Cell ◽  
Future Work ◽  
The Impact

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases.

scholarly journals Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Hao Zhou ◽  
Wei Liu ◽  
Yongming Zhou ◽  
Zhenya Hong ◽  
Jian Ni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Leukemia Cell ◽  
Treatment Strategies ◽  
Network Analyses ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Its therapy has not significantly improved during the past four decades despite intense research efforts. New molecularly targeted therapies are in great need. The proto-oncogene c-Myc (MYC) is an attractive target due to its transactivation role in multiple signaling cascades. Deregulation of the MYC is considered one of a series of oncogenic events required for tumorigenesis. However, limited knowledge is available on which mechanism underlie MYC dysregulation and how long non-coding RNAs (lncRNAs) are involved in MYC dysregulation in AML. Methods AML microarray chips and public datasets were screened to identify novel lncRNA GAS6-AS1 was dysregulated in AML. Gain or loss of functional leukemia cell models were produced, and in vitro and in vivo experiments were applied to demonstrate its leukemogenic phenotypes. Interactive network analyses were performed to define intrinsic mechanism. Results We identified GAS6-AS1 was overexpressed in AML, and its aberrant function lead to more aggressive leukemia phenotypes and poorer survival outcomes. We revealed that GAS6-AS1 directly binds Y-box binding protein 1 (YBX1) to facilitate its interaction with MYC, leading to MYC transactivation and upregulation of IL1R1, RAB27B and other MYC target genes associated with leukemia progression. Further, lentiviral-based GAS6-AS1 silencing inhibited leukemia progression in vivo. Conclusions Our findings revealed a previously unappreciated role of GAS6-AS1 as an oncogenic lncRNA in AML progression and prognostic prediction. Importantly, we demonstrated that therapeutic targeting of the GAS6-AS1/YBX1/MYC axis inhibits AML cellular propagation and disease progression. Our insight in lncRNA associated MYC-driven leukemogenesis may contribute to develop new anti-leukemia treatment strategies.

Retinoic acid promotes differentiation of photoreceptors in vitro

Development ◽  
1994 ◽  
Vol 120 (8) ◽  
pp. 2091-2102 ◽  
Author(s):  
M.W. Kelley ◽  
J.K. Turner ◽  
T.A. Reh
Keyword(s):  
Retinoic Acid ◽  
Cell Fate ◽  
Amacrine Cells ◽  
Photoreceptor Cells ◽  
Neonatal Rat ◽  
Cell Commitment ◽  
Dose Dependent ◽  
Number Of Cells

The results of several recent studies have demonstrated that cell commitment and differentiation in the developing vertebrate retina are influenced by cell-cell interactions within the microenvironment. Retinoic acid has been shown to influence cell fates during development of the nervous system, and retinoic acid has been detected in the embryonic retina. To determine whether retinoic acid mediates the differentiation of specific neuronal phenotypes during retinal histogenesis, we treated dissociated cell cultures of embryonic and neonatal rat retina with varying concentrations of all-trans or 9-cis retinoic acid and analyzed the effects on cell fate using neuron and photoreceptor-specific antibodies. Addition of exogenous retinoic acid caused a dose-dependent, specific increase in the number of cells that developed as photoreceptors in culture throughout the period of retinal neurogenesis. In the same cultures, retinoic acid also caused a dose-dependent decrease in the number of cells that developed as amacrine cells. Also, results of double-labeled immunohistochemical studies using bromodeoxyuridine demonstrated that the primary effect of retinoic acid was to influence progenitor cells to develop as newly generated rod photoreceptors. Since retinoic acid and at least one of the retinoic acid receptors (RAR alpha) have been localized to the developing neural retina, these results suggest that retinoic acid may play a role in the normal development of photoreceptor cells in vivo.

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