Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control

2021 ◽  
Author(s):  
Byongsun Lee ◽  
Seungjae Lee ◽  
Younggwang Lee ◽  
Yongjin Park ◽  
Jaekyung Shim
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Membrane ◽  
Target Genes ◽  
Janus Kinase ◽  
C2c12 Cells ◽  
Specific Gene ◽  
Lamin A ◽  
Stat3 Signaling ◽  
Exact Function ◽  
Induced Apoptosis

Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery–Dreifuss muscular dystrophy (EDMD). There has been accumulating evidence that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has still less revealing. Here, we have shown that emerin downregulates Signal transducer and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus-kinase (JAK). Deletion mutation experiments showed that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacted directly and co-localized with STAT3 in the nuclear membrane. Emerin knockdown induced STAT3 target genes Bcl2 and Survivin to increase cell survival signals and suppress hydrogen peroxide-induced apoptosis in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin by assembling with BAF and lamin A/C acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induced STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and could be a new therapeutic target for treatment.

scholarly journals Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control

2021 ◽  
Vol 22 (13) ◽  
pp. 6669
Author(s):  
Byongsun Lee ◽  
Seungjae Lee ◽  
Younggwang Lee ◽  
Yongjin Park ◽  
Jaekyung Shim
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Membrane ◽  
Target Genes ◽  
Janus Kinase ◽  
C2c12 Cells ◽  
Specific Gene ◽  
Lamin A ◽  
Stat3 Signaling ◽  
Exact Function ◽  
Muscle Homeostasis

Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery-Dreifuss muscular dystrophy (EDMD). There has been accumulating evidence that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has still less revealing. Here, we have shown that emerin downregulates signal transducers and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus-kinase (JAK). Deletion mutation experiments showed that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacted directly and co-localized with STAT3 in the nuclear membrane. Emerin knockdown induced STAT3 target genes Bcl2 and Survivin to increase cell survival signals and suppress hydrogen peroxide-induced cell death in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin by assembling with BAF and lamin A/C acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induced STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and could be a new therapeutic target for treatment.

Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3α

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3339-3347 ◽  
Author(s):  
Björn Lamprecht ◽  
Stephan Kreher ◽  
Ioannis Anagnostopoulos ◽  
Korinna Jöhrens ◽  
Giovanni Monteleone ◽  
...  
Keyword(s):  
T Cells ◽  
Hodgkin Lymphoma ◽  
Target Genes ◽  
Immune Escape ◽  
Gene Expression Pattern ◽  
Death Receptor ◽  
Treg Cells ◽  
Specific Gene ◽  
Aberrant Expression ◽  
Induced Apoptosis

Abstract The malignant Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (HL) are derived from mature B cells, but have lost a considerable part of the B cell–specific gene expression pattern. Consequences of such a lineage infidelity for lymphoma pathogenesis are currently not defined. Here, we report that HRS cells aberrantly express the common cytokine-receptor γ-chain (γc) cytokine IL-21, which is usually restricted to a subset of CD4+ T cells, and the corresponding IL-21 receptor. We demonstrate that IL-21 activates STAT3 in HRS cells, up-regulates STAT3 target genes, and protects HRS cells from CD95 death receptor–induced apoptosis. Furthermore, IL-21 is involved in up-regulation of the CC chemokine macrophage-inflammatory protein-3α (MIP-3α) in HRS cells. MIP-3α in turn attracts CCR6+CD4+CD25+FoxP3+CD127lo regulatory T cells toward HRS cells, which might favor their immune escape. Together, these data support the concept that aberrant expression of B lineage–inappropriate genes plays an important role for the biology of HL tumor cells.

MiR-189 Exerts Anticancer Activity Through Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) Pathway in Non-Small Cell Lung Cancer

2021 ◽  
Vol 11 (12) ◽  
pp. 2421-2426
Author(s):  
Hongyun Ji ◽  
Hui Lu ◽  
Feng Li ◽  
Ying Qu ◽  
Qing Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Janus Kinase ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Stat3 Signaling ◽  
Induced Apoptosis

Non-small cell lung cancer (NSCLC) remains a threat to human health but its etiology remains unclear. MicroRNAs (miRNAs) are involved in NSCLC progression. This study aims to elucidate the mechanism by how exosomal miR-189 functions in NSCLC. After identification, BMSCs were co-cultured with NSCLC cells which were then transfected with miR-189 mimics followed by analysis of the expression of JAK2/Stat3 proteins and miR-189, cell migration and invasion by Transwell assay, cell viability by MTT assay, apoptosis by flow cytometry. miR-189 is downregulated in NSCLC cells and tissues. miR-189 overexpression inhibited the phosphorylation of JAK2/Stat3 and suppressed malignant characteristics of cancer cells and induced apoptosis. Co-culture with BMSCs and NSCLC cells elevated miR-189 level and inactivated JAK2/STAT3 signaling, thereby suppressing malignant characteristics of cancer cells. In conclusion, BMSCs carrying miR-189 restrain NSCLC progression by blocking JAK2/STAT3 signaling, which may help development of gene therapy for NSCLC.

The cell cycle dependent mislocalisation of emerin may contribute to the Emery-Dreifuss muscular dystrophy phenotype

2002 ◽  
Vol 115 (2) ◽  
pp. 341-354 ◽  
Author(s):  
Elizabeth A. L. Fairley ◽  
Andrew Riddell ◽  
Juliet A. Ellis ◽  
John Kendrick-Jones
Keyword(s):  
Cell Cycle ◽  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Transmembrane Domain ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Wild Type ◽  
Cycle Dependent ◽  
Mutant Forms

Emerin is the nuclear membrane protein defective in X-linked Emery-Dreifuss muscular dystrophy (X-EDMD). The majority of X-EDMD patients have no detectable emerin. However, there are cases that produce mutant forms of emerin, which can be used to study its function. Our previous studies have shown that the emerin mutants S54F, P183T, P183H, Del95-99, Del236-241 (identified in X-EDMD patients) are targeted to the nuclear membrane but to a lesser extent than wild-type emerin. In this paper, we have studied how the mislocalisation of these mutant emerins may affect nuclear functions associated with the cell cycle using flow cytometry and immunofluorescence microscopy. We have established that cells expressing the emerin mutant Del236-241 (a deletion in the transmembrane domain), which was mainly localised in the cytoplasm, exhibited an aberrant cell cycle length. Thereafter, by examining the intracellular localisation of endogenously expressed lamin A/C and exogenously expressed wild-type and mutant forms of emerin after a number of cell divisions, we determined that the mutant forms of emerin redistributed endogenous lamin A/C. The extent of lamin A/C redistribution correlated with the amount of EGFP-emerin that was mislocalised. The amount of EGFP-emerin mislocalized, in turn, was associated with alterations in the nuclear envelope morphology. The nuclear morphology and redistribution of lamin A/C was most severely affected in the cells expressing the emerin mutant Del236-241.It is believed that emerin is part of a novel nuclear protein complex consisting of the barrier-to-autointegration factor (BAF), the nuclear lamina, nuclear actin and other associated proteins. The data presented here show that lamin A/C localisation is dominantly directed by its interaction with certain emerin mutants and perhaps wild-type emerin as well. These results suggest that emerin links A-type lamins to the nuclear envelope and that the correct localisation of these nuclear proteins is important for maintaining cell cycle timing.

scholarly journals The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1921 ◽  
Author(s):  
Olivier Mansier ◽  
Valérie Prouzet-Mauléon ◽  
Gwénaële Jégou ◽  
Kim Barroso ◽  
Diana Pelizzari Raymundo ◽  
...  
Keyword(s):  
Target Genes ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Janus Kinase ◽  
Expression Level ◽  
Mutant Proteins ◽  
Subsequent Activation ◽  
Induced Apoptosis ◽  
Er Homeostasis ◽  
The Impact

Background: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase – Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis. Methods: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. Results: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. Conclusions: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes.

scholarly journals Myne-1, a spectrin repeat transmembrane protein of the myocyte inner nuclear membrane, interacts with lamin A/C

2002 ◽  
Vol 115 (1) ◽  
pp. 61-70 ◽  
Author(s):  
John M. K. Mislow ◽  
Marian S. Kim ◽  
Dawn Belt Davis ◽  
Elizabeth M. McNally
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Lamin A ◽  
Spectrin Repeat ◽  
Inner Nuclear Membrane ◽  
C Terminus

Mutations in the genes encoding the inner nuclear membrane proteins lamin A/C and emerin produce cardiomyopathy and muscular dystrophy in humans and mice. The mechanism by which these broadly expressed gene products result in tissue-specific dysfunction is not known. We have identified a protein of the inner nuclear membrane that is highly expressed in striated and smooth muscle. This protein, myne-1 (myocyte nuclear envelope), is predicted to have seven spectrin repeats, an interrupted LEM domain and a single transmembrane domain at its C-terminus. We found that myne-1 is expressed upon early muscle differentiation in multiple intranuclear foci concomitant with lamin A/C expression. In mature muscle, myne-1 and lamin A/C are perfectly colocalized, although colocalization with emerin is only partial. Moreover, we show that myne-1 and lamin A/C coimmunoprecipitate from differentiated muscle in vitro. The muscle-specific inner nuclear envelope expression of myne-1, along with its interaction with lamin A/C, indicates that this gene is a potential mediator of cardiomyopathy and muscular dystrophy.

scholarly journals Mechanisms of allelic and clinical heterogeneity of lamin A/C phenotypes

2018 ◽  
Vol 50 (9) ◽  
pp. 694-704 ◽  
Author(s):  
Jelena Perovanovic ◽  
Eric P. Hoffman
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Structural Model ◽  
Terminal Differentiation ◽  
Dominant Negative ◽  
Single Amino Acid ◽  
Lamin A ◽  
Gain Of Function ◽  
Heterochromatin Formation

Mutations in the lamin A/C ( LMNA) gene cause a broad range of clinical syndromes that show tissue-restricted abnormalities of post mitotic tissues, such as muscle, nerve, heart, and adipose tissue. Mutations in other nuclear envelope proteins cause clinically overlapping disorders. The majority of mutations are dominant single amino acid changes (toxic protein produced by the single mutant gene), and patients are heterozygous with both normal and abnormal proteins. Experimental support has been provided for different models of cellular pathogenesis in nuclear envelope diseases, including changes in heterochromatin formation at the nuclear membrane (epigenomics), changes in the timing of steps during terminal differentiation of cells, and structural abnormalities of the nuclear membrane. These models are not mutually exclusive and may be important in different cells at different times of development. Recent experiments using fusion proteins of normal and mutant lamin A/C proteins fused to a bacterial adenine methyltransferase (DamID) provided compelling evidence of mutation-specific perturbation of epigenomic imprinting during terminal differentiation. These gain-of-function properties include lineage-specific ineffective genomic silencing during exit from the cell cycle (heterochromatinization), as well as promiscuous initiation of silencing at incorrect places in the genome. To date, these findings have been limited to a few muscular dystrophy and lipodystrophy LMNA mutations but seem shared with a distinct nuclear envelope disease, emerin-deficient muscular dystrophy. The dominant-negative structural model and gain-of-function epigenomic models for distinct LMNA mutations are not mutually exclusive, and it is likely that both models contribute to aspects of the many complex clinical phenotypes observed.

scholarly journals A Sesquiterpenoid from Farfarae Flos Induces Apoptosis of MDA-MB-231 Human Breast Cancer Cells through Inhibition of JAK–STAT3 Signaling

Biomolecules ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 278 ◽  
Author(s):  
Hyeri Jang ◽  
Hyejin Ko ◽  
Kwangho Song ◽  
Yeong Kim
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Target Genes ◽  
Intraperitoneal Administration ◽  
Breast Cancers ◽  
Anticancer Effect ◽  
Stat3 Signaling ◽  
Induced Apoptosis ◽  
Transcription 3 ◽  
Anticancer Compound

Triple-negative breast cancers (TNBCs) are hard-to-treat breast tumors with poor prognosis, which need to be treated by chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in proliferation, metastasis, and invasion of cancer cells. Therefore, research on searching for promising compounds with metabolism that suppress phosphorylation or transcription of STAT3 in TNBC cells is important. Farfarae Flos is well known as a traditional medicine for treating inflammation. However, few studies have shown that sesquiterpenoids from Farfarae Flos have an anticancer effect. In this study, efficient separation methods and an MTT assay were conducted to isolate an anticancer compound from Farfarae Flos against TNBC MDA-MB-231 cells. Here, 7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a compound isolated from Farfarae Flos showed a potent cytotoxic effect on MDA-MB-231 cells. ECN inhibited JAK–STAT3 signaling and suppressed the expression of STAT3 target genes. In addition, ECN induced apoptosis through both extrinsic and intrinsic pathways. Furthermore, we investigated that ECN inhibited the growth of tumors by intraperitoneal administration in mice injected with MDA-MB-231 cells. Therefore, ECN can be an effective chemotherapeutic agent for breast cancer treatment.

scholarly journals Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

2012 ◽  
Vol 90 (10) ◽  
pp. 1354-1363 ◽  
Author(s):  
Chunja Lee ◽  
David S. Riddick
Keyword(s):  
Growth Hormone ◽  
Cytochrome P450 ◽  
Aryl Hydrocarbon Receptor ◽  
Target Genes ◽  
Janus Kinase ◽  
Specific Gene ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Aryl Hydrocarbon ◽  
Signaling Components

The aryl hydrocarbon receptor (AHR) has physiological roles in the absence of exposure to exogenous ligands, and mediates adaptive and toxic responses to the environmental pollutant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD). A readily metabolized AHR agonist, 3-methylcholanthrene, disrupts the expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). Using TCDD as an essentially nonmetabolized AHR agonist, and Ahr −/− mice as the preferred model to determine the AHR-dependence of biological responses, we now show that 2 mouse hepatic STAT5b target genes, Cyp2d9, and major urinary protein 2 (Mup2), are suppressed by TCDD in an AHR-dependent manner. TCDD also decreased hepatic mRNA levels for GH receptor, Janus kinase 2, and STAT5a/b with AHR-dependence. Without inducing selected hepatic inflammatory markers, TCDD caused AHR-dependent induction of Cyp1a1 and NADPH-cytochrome P450 oxidoreductase (Por) and suppression of Cyp3a11. In vehicle-treated mice, basal mRNA levels for CYP2D9, CYP3A11, POR, serum amyloid protein P, and MUP2 were influenced by Ahr genetic status. We conclude that AHR activation per se leads to dysregulation of hepatic GH signaling components and suppression of some, but not all, STAT5b target genes.

scholarly journals ATRT-03. IDENTIFICATION OF microRNA-BASED PROGNOSTIC BIOMARKERS AND CANDIDATE THERAPEUTIC AGENTS FOR ATYPICAL TERATOID/RHABDOID TUMOR

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii275-iii276
Author(s):  
Yang Zhang ◽  
Jianguo Xu
Keyword(s):  
Target Genes ◽  
Kinase Inhibitor ◽  
Therapeutic Agents ◽  
Rhabdoid Tumor ◽  
Janus Kinase ◽  
Prognostic Biomarkers ◽  
Atypical Teratoid Rhabdoid Tumor ◽  
Overlapping Genes ◽  
Hub Genes ◽  
Atypical Teratoid

Abstract BACKGROUND MicroRNA (miRNA) has been found to be involved in development of many malignant pediatric brain tumors, including atypical teratoid/rhabdoid tumor (AT/RT) that is highly aggressive and carries a dismal prognosis. The current study investigated the potential value of miRNAs and pivotal genes associated with AT/RT using bioinformatics analysis, aiming to identify new prognostic biomarkers and candidate drugs for AT/RT patients. METHODS Differentially expressed miRNAs (DEMs) and genes (DEGs) between AT/RT and normal control samples were obtained from GEO database. The target genes of DEMs were predicted via TargetScanHuman7.2 and miRDB, and then intersected with DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of overlapping genes were conducted, followed by construction of protein-protein interaction network. Hub genes were determined by Cytoscape software, and their prognostic values were evaluated using Kaplan-Meier analysis. Connectivity Map database was used to identify latent therapeutic agents. RESULTS A total of 11 DEMs (hsa-miR-1224-5p, hsa-miR-128-3p, hsa-miR-17-5p, hsa-miR-18b-5p, hsa-miR-29c-5p, hsa-miR-329-3p, hsa-miR-379-5p, hsa-miR-433-3p, hsa-miR-488-5p, hsa-miR-656-3p and hsa-miR-885-5p) were screened. By intersecting 3275 predicted target genes and 925 DEGs, we finally identified 226 overlapping genes that were enriched in pathways in cancer and MAPK signaling pathway. Four hub genes (GRIA2, NRXN1, SLC6A1 and SYT1) were significantly associated with the overall survival of AT/RT patients. Candidate drugs included histone deacetylase inhibitor (givinostat), DNA synthesis inhibitor (floxuridine), cyclin-dependent kinase inhibitor (purvalanol) and janus kinase inhibitor (lestaurtinib). CONCLUSION In summary, this study systematically analyzed AT/RT-related miRNAs and pivotal genes to provide novel prognostic biomarkers and potential therapeutic agents.

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