Xrel3/XrelA attenuates β-catenin-mediated transcription during mesoderm formation in Xenopus embryos

2011 ◽  
Vol 435 (1) ◽  
pp. 247-257 ◽  
Author(s):  
Mark W. L. Kennedy ◽  
Kenneth R. Kao
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Marginal Zone ◽  
Ectopic Expression ◽  
Nuclear Factor Κb ◽  
Mesoderm Induction ◽  
Mesoderm Cell ◽  
Mesoderm Formation

In Xenopus laevis embryonic development, activation of the Wnt/β-catenin pathway promotes mesoderm cell fate determination via Xnr (Xenopus nodal-related) expression. We have demonstrated previously that Rel/NF-κB (nuclear factor κB) proteins expressed in presumptive ectoderm limit the activity of Xnrs to the marginal zone of embryos during mesoderm induction, which assists to distinguish mesoderm from ectoderm. The mechanism of this regulation, however, is unknown. In the present study, we investigated whether Rel/NF-κB proteins are able to modulate mesoderm formation by mediating Wnt/β-catenin signalling. We determined that ectopic expression of XrelA or Xrel3 in the dorsal marginal zone perturbed dorsal mesoderm formation by down-regulating multiple Wnt/β-catenin target genes including Xnr3, Xnr5 and Xnr6. Ventral co-expression of XrelA or Xrel3 with either wild-type β-catenin or constitutively active β-cateninS37A abrogated β-catenin-induced axis duplication and attenuated β-catenin-stimulated reporter transcription. Lastly, we provide evidence that Xrel3, but not XrelA, can interact with β-catenin without affecting the association of β-catenin with other transcriptional co-activators in vitro. Both Xrel3 and XrelA, however, prevented the accumulation, in nuclei, of exogenously expressed and endogenous β-catenin in vivo. These results suggest that Rel proteins are able to bind β-catenin and attenuate β-catenin-mediated transcription by nuclear exclusion.

scholarly journals Eμ-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-κB pathways generating marginal zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4158-4168 ◽  
Author(s):  
Zhaoyang Li ◽  
Hongsheng Wang ◽  
Liquan Xue ◽  
Dong-Mi Shin ◽  
Derry Roopenian ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Target Genes ◽  
Marginal Zone ◽  
Nuclear Factor Κb ◽  
Tissue Type ◽  
Constitutive Activation ◽  
Lymphocyte Responses

Abstract BCL10, required for nuclear factor κB (NF-κB) activation during antigen-driven lymphocyte responses, is aberrantly expressed in mucosa-associated lymphoid tissue-type marginal zone (MZ) lymphomas because of chromosomal translocations. Eμ-driven human BCL10 transgenic (Tg) mice, which we created and characterize here, had expanded populations of MZ B cells and reduced follicular and B1a cells. Splenic B cells from Tg mice exhibited constitutive activation of both canonical and noncanonical NF-κB signaling pathways is associated with increased expression of NF-κB target genes. These genes included Tnfsf13b, which encodes the B-cell activating factor (BAFF). In addition, levels of BAFF were significantly increased in sera from Tg mice. MZ B cells of Tg mice exhibited reduced turnover in vivo and enhanced survival in vitro, indicative of lymphoaccumulation rather than lymphoproliferation as the cause of MZ expansion. In vivo antibody responses to both T-independent, and especially T-dependent, antigens were significantly reduced in Tg mice. Mortality was accelerated in Tg animals, and some mice older than 8 months had histologic and molecular findings indicative of clonal splenic MZ lymphoma. These results suggest that, in addition to constitutive activation of BCL10 in MZ B cells, other genetic factors or environmental influences are required for short latency oncogenic transformation.

Misexpression of chick Vg1 in the marginal zone induces primitive streak formation

Development ◽  
1997 ◽  
Vol 124 (24) ◽  
pp. 5127-5138 ◽  
Author(s):  
S.B. Shah ◽  
I. Skromne ◽  
C.R. Hume ◽  
D.S. Kessler ◽  
K.J. Lee ◽  
...  
Keyword(s):  
Marginal Zone ◽  
Ectopic Expression ◽  
Primitive Streak ◽  
Axis Formation ◽  
Mesoderm Induction ◽  
Cell Fates ◽  
Signalling Molecules ◽  
Posterior Area ◽  
Area Pellucida

In the chick embryo, the primitive streak is the first axial structure to develop. The initiation of primitive streak formation in the posterior area pellucida is influenced by the adjacent posterior marginal zone (PMZ). We show here that chick Vg1 (cVg1), a member of the TGFbeta family of signalling molecules whose homolog in Xenopus is implicated in mesoderm induction, is expressed in the PMZ of prestreak embryos. Ectopic expression of cVg1 protein in the marginal zone chick blastoderms directs the formation of a secondary primitive streak, which subsequently develops into an ectopic embryo. We have used cell marking techniques to show that cells that contribute to the ectopic primitive streak change fate, acquiring two distinct properties of primitive streak cells, defined by gene expression and cell movements. Furthermore, naive epiblast explants exposed to cVg1 protein in vitro acquire axial mesodermal properties. Together, these results show that cVg1 can mediate ectopic axis formation in the chick by inducing new cell fates and they permit the analysis of distinct events that occur during primitive streak formation.

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 Growth Suppression by Acute PromyelocyticLeukemia-Associated Protein PLZF Is Mediated by Repression ofc-mycExpression

2003 ◽  
Vol 23 (24) ◽  
pp. 9375-9388 ◽  
Author(s):  
Melanie J. McConnell ◽  
Nathalie Chevallier ◽  
Windy Berkofsky-Fessler ◽  
Jena M. Giltnane ◽  
Rupal B. Malani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Target Genes ◽  
Ectopic Expression ◽  
Growth Suppression ◽  
Quiescent State ◽  
Cycle Arrest

ABSTRACT The transcriptional repressor PLZF was identified by its translocation with retinoic acid receptor alpha in t(11;17) acute promyelocytic leukemia (APL). Ectopic expression of PLZF leads to cell cycle arrest and growth suppression, while disruption of normal PLZF function is implicated in the development of APL. To clarify the function of PLZF in cell growth and survival, we used an inducible PLZF cell line in a microarray analysis to identify the target genes repressed by PLZF. One prominent gene identified was c-myc. The array analysis demonstrated that repression of c-myc by PLZF led to a reduction in c-myc-activated transcripts and an increase in c-myc-repressed transcripts. Regulation of c-myc by PLZF was shown to be both direct and reversible. An interaction between PLZF and the c-myc promoter could be detected both in vitro and in vivo. PLZF repressed the wild-type c-myc promoter in a reporter assay, dependent on the integrity of the binding site identified in vitro. PLZF binding in vivo was coincident with a decrease in RNA polymerase occupation of the c-myc promoter, indicating that repression occurred via a reduction in the initiation of transcription. Finally, expression of c-myc reversed the cell cycle arrest induced by PLZF. These data suggest that PLZF expression maintains a cell in a quiescent state by repressing c-myc expression and preventing cell cycle progression. Loss of this repression through the translocation that occurs in t(11;17) would have serious consequences for cell growth control.

Exosomes derived miR-454-3P to promote the progression of colorectal cancer via MIER1-mediated Notch signaling activation.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15108-e15108
Author(s):  
Dawei Li ◽  
Senglin Zhao ◽  
Ye Xu ◽  
Xinxiang Li ◽  
Sanjun Cai
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Early Response ◽  
Mesoderm Induction ◽  
Cancer Proliferation ◽  
Mesenchymal Transition ◽  
Mechanistic Investigation

e15108 Background: Mesoderm induction early response 1 (MIER1) was downregulated and predicted poor prognosis in CRC patients. However, the mechanisms of the down regulation of MIER1 in CRC remained unclear. Increasing evidence indicates that dysregulation of microRNAs promotes the progression of cancer through the repression of tumour suppressors.Here, we identified exosomes derived miR-454-3p as a novel regulator of MIER1 in CRC. Methods: The effect of miR-454-3p expression on cancer proliferation and metastasis was assessed in cells by altering the expression of miR-454-3p in vitro and in vivo. Mechanistic investigation was carried out by using cell and molecular biology approaches. Results: Functionally, ectopic expression or silencing of exosomes derived miR-454-3P, respectively, promoted or inhibited CRC cell proliferation, colony formation and cell cycle transition, as well as enhanced or prevented the invasion, metastasis of CRC cells and epithelial to mesenchymal transition of CRC cells in vitro and in vivo. Molecularly, exosomes derived miR-454-3P functioned as an onco-miRNA by activating the MIER1-regulated NOTCH pathway. Overexpression or silencing of MIER1 could partially reverse the effects of the overexpression or repression of exosomes derived miR-454-3P on CRC progress caused by activation of the NOTCH pathway in vitro and in vivo. Clinically, high miR-454-3P expression predicted poor survival in CRC patients, especially combined with low MIER1 expression. Conclusions: Collectively, we identified exosomes derived miR- 454-3p as an onco-miRNA, which acts by directly repressing MIER1 in CRC.

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 442: Epigenetic Regulation of Ezh2 in Direct Human Cardiac Reprogramming

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yang Zhou ◽  
Yawen Tang ◽  
Lianzhong Zhao ◽  
Rui Lu ◽  
Jianyi Zhang
Keyword(s):  
Cardiovascular Disease ◽  
Cell Fate ◽  
Epigenetic Regulation ◽  
Ectopic Expression ◽  
The United States ◽  
Inhibitory Effect ◽  
Loss Of Function ◽  
Lower Efficiency

Cardiovascular disease is still the leading cause of death in the United States. Due to the limited regenerative capacity of adult hearts, the damage caused by heart injury could not be reversed and often progressed into heart failure. In need of cardiovascular disease treatment, many therapies aimed at either cell transplantation or cell regeneration have been proposed. Direct reprogramming of somatic cells into induced cardiomyocytes (iCMs) is considered to be a promising strategy for regenerative medicine. The induction of cardiomyocytes from non-myocytes has been achieved efficiently via ectopic expression of reprogramming factors both in vitro and in vivo with mice models. However, as human cells are more resistant to the reprogramming process, the generation of human iCMs (hiCMs) has been restricted by the factor that using more complex cocktails generated only functionally immature cells with lower efficiency and longer conversion time. The inefficiency of hiCMs production called for the identification and elucidation of underlying species-specific regulatory mechanisms in human, and removal of the additional epigenetic barriers which might be damping the hiCMs reprogramming. Here, we identified a human-specific epigenetic barrier, Enhancer of zesta homolog 2 (EZH2), via an unbiased loss-of-function screening. With the knockdown of EZH2, the hiCM reprogramming efficiency was significantly increased, accompanied with profound repression of collagen and extracellular matrix genes, which are related to the formation of fibrosis. Consistently, Inhibition of EZH2 catalytic activity via small molecules promotes hiCM reprogramming, suggesting that EZH2’s inhibitory effect was mediated by epigenetic regulation of histone modifications. Therefore, our study revealed a previously unrecognized regulatory mechanism of human cardiac reprogramming, which allows us to overcome the fibroblast fate barriers and ease the cardiac cell fate conversion.

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 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 ENO3 Inhibits Growth and Metastasis of Hepatocellular Carcinoma via Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Honglei Cui ◽  
Danfeng Guo ◽  
Xiaodan Zhang ◽  
Yaohua Zhu ◽  
Zhihui Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Noncancerous Tissue ◽  
Mesenchymal Transition ◽  
Proliferation And Metastasis ◽  
Hcc Cells

β-enolase (ENO3) is a metalloenzyme that functions during glycolysis and has been revealed ectopic expression in different cancers. However, the function and underlying modulatory mechanisms of ENO3 in hepatocellular carcinoma (HCC) are still elusive. Here, we discovered that ENO3 was remarkably down-regulated in human HCC tissue in contrast to those in noncancerous tissue. Moreover, low expression of ENO3 was related to the poor prognosis of HCC patients. Overexpression of ENO3 suppressed proliferative, migratory, and invasive abilities of HCC cells both in vitro and in vivo, whereas knocking down ENO3 led to the opposite effect. In addition, we revealed that ENO3 repressed the epithelial-mesenchymal transition (EMT) process with its biomarker variations. Mechanistic research unveiled that ENO3 suppressed the Wnt/β-catenin signal, which subsequently modulated the transcription of its target genes associated with the proliferation and metastasis capacity of HCC cells. Taken together, our study uncovered that ENO3 acted as a tumor inhibitor in HCC development and implied ENO3 as a promising candidate for HCC treatment.

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