Egr2 and Egr3 are the unique regulators for systemic autoimmunity

Sumitomo, Shuji; Fujio, Keishi; Okamura, Tomohisa; Yamamoto, Kazuhiko

doi:10.4161/jkst.23952

Cited by 18 publications

(22 citation statements)

References 16 publications

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“…We also examined the mechanisms involved in pro-inflammatory phenotype conferred by Egr2 gene silencing in VSMC. Previous reports in myeloid cells showed that Egr2 induces suppressor of cytokine signaling-1 ( Socs1) and Socs 2, negative regulators of cytokine signaling, to inhibit inflammation 45, 46 . Because our RNA-seq data revealed downregulation of Socs 1 in db/dbVSMC (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Vascular Smooth Muscle Cell Dysfunction Under Diabetic Conditions by miR-504

Reddy

Das

Chen

et al. 2016

ATVB

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Objectives Diabetes accelerates pro-atherogenic and pro-inflammatory phenotype of VSMC associated with vascular complications. Evidence shows that microRNAs (miRNAs) play key roles in VSMC functions, but their role under diabetic conditions is unclear. We profiled miRNAs in VSMC from diabetic mice and examined their role in VSMC dysfunction. Approach and Results High throughput small RNA-sequencing identified 135 differentially expressed miRNAs in VSMC from type-2 diabetic db/db mice (db/dbVSMC) versus non-diabetic db/+ mice. Several of these miRNAs were known to regulate VSMC functions. We further focused on miR-504, because it was highly upregulated in db/dbVSMC, and its function in VSMC is unknown. miR-504 and its host gene Fgf13 were significantly increased in db/dbVSMC and in aortas from db/db mice. Bioinformatics analysis predicted that miR-504 targets including signaling adaptor Grb10 and transcription factor Egr2 could regulate growth factor signaling. We experimentally validated Grb10 and Egr2 as novel targets of miR-504. Overexpression of miR-504 in VSMC inhibited contractile genes, and enhanced ERK1/2 activation, proliferation and migration. These effects were blocked by miR-504 inhibitors. Grb10 knockdown mimicked miR-504 functions and increased inflammatory genes. Egr2 knockdown inhibited anti-inflammatory Socs1 and increased pro-inflammatory genes. Furthermore, high-glucose and palmitic acid upregulated miR-504 and inflammatory genes, but downregulated Grb10. Conclusions Diabetes mis-regulates several miRNAs including miR-504 that can promote VSMC dysfunction. Since changes in many of these miRNAs are sustained in diabetic VSMC even after in vitro culture, they may be involved in metabolic memory of vascular complications. Targeting such mechanisms could offer novel therapeutic strategies for diabetic complications.

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Section: Resultsmentioning

confidence: 99%

Regulation of Vascular Smooth Muscle Cell Dysfunction Under Diabetic Conditions by miR-504

Reddy

Das

Chen

et al. 2016

ATVB

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“…However, it is noteworthy that Egr3 is also known to be important in the function of cells other than those of muscle cell type. Indeed, Egr3 can function in the development of neurons (Quach et al, ), activation of T‐cells (Safford et al, ; Sumitomo et al, ,) and vascular endothelial cells (Suehiro et al, ), and macrophage differentiation (Carter and Tourtellotte, ). In this regard, previous reports have described that muscle injury by CTX is neurotoxic (Harris, ).…”

Section: Discussionmentioning

confidence: 99%

“…Accumulated evidence has revealed the biological role of Egr3 in mammalian cells. Examples of some roles are activation and cytokine production in T‐cells (Safford et al, ; Sumitomo et al, ,), neuronal adaptation (O'Donovan et al, ), and transduction of growth signaling in endothelial cells (Suehiro et al, ). Moreover, Egr3 has been implicated in the proliferation of mammalian cells such as hematopoietic stem cells (Cheng et al, ) and T‐cells (Xi et al, ).…”

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confidence: 99%

“…The satellite cell function is regulated by many signaling molecules. Recent studies have uncovered regulatory interactions between Egr3 and several molecules, including signal transducers and activators of transcription (STAT) (Li et al, ; Sumitomo et al, ), activator protein‐1 (Li et al, ; Sumitomo et al, ) and nuclear factor‐kappa B (NF‐кB) (Wieland et al, ). These latter molecules are known to regulate satellite cell proliferation and self‐renewal (Lehtinen et al, ; Guttridge et al, ; Kurosaka and Machida, ; Ogura et al, ; Price et al, ; Tierney et al, ; Ogura et al, ).…”

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confidence: 99%

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Early Growth Response 3 (Egr3) Contributes a Maintenance of C2C12 Myoblast Proliferation

Kurosaka

Ogura

Funabashi

et al. 2016

Journal Cellular Physiology

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Satellite cell proliferation is a crucially important process for adult myogenesis. However, its regulatory mechanisms remain unknown. Early growth response 3 (Egr3) is a zinc-finger transcription factor that regulates different cellular functions. Reportedly, Egr3 interacts with multiple signaling molecules that are also known to regulate satellite cell proliferation. Therefore, it is possible that Egr3 is involved in satellite cell proliferation. Results of this study have demonstrated that Egr3 transcript levels are upregulated in regenerating mouse skeletal muscle after cardiotoxin injury. Using C2C12 myoblast culture (a model of activated satellite cells), results show that inhibition of Egr3 by shRNA impairs the myoblast proliferation rate. Results also show reduction of NF-кB transcriptional activity in Egr3-inhibited cells. Inhibition of Egr3 is associated with an increase in annexin V cell fraction and apoptotic protein activity including caspase-3 and caspase-7, and Poly-ADP ribose polymerase. By contrast, the reduction of cellular proliferation by inhibition of Egr3 was partially recovered by treatment of pan-caspase inhibitor Z-VAD-FMK. Collectively, these results suggest that Egr3 is involved in myoblast proliferation by interaction with survival signaling. J. Cell. Physiol. 232: 1114-1122, 2017. © 2016 Wiley Periodicals, Inc.

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“…EGR3 promotes the transformation of undifferentiated myotubes into intrafusal fiber [29]. EGR3 specifically induces the expression of TGF-β1 in CD4+ T cells and enhances the phosphorylation of STAT3 associated with TGF-β1 transcription [30]. That is to say, EGR3 is a transcription factor related to the expression of TGF-β1 and regulatory activity in humans.…”

Section: Discussionmentioning

confidence: 99%

Chimeric Antigen Receptor-T Cells with 4-1BB Co-Stimulatory Domain Present a Superior Treatment Outcome than Those with CD28 Domain Based on Bioinformatics

et al. 2018

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Background: The second-generation CD19-chimeric antigen receptor (CAR)-T co-stimulatory domain that is commonly used in clinical practice is CD28 or 4-1BB. Previous studies have shown that the persistence of CAR-T in the 4-1BB co-stimulatory domain appears to be longer. Methods: The expression profile data of GSE65856 were obtained from GEO database. After data preprocessing, the differentially expressed genes (DEGs) between the mock CAR versus CD19-28z CAR T cells and mock CAR versus CD19-BBz CAR T cells were identified using the limma package. Subsequently, functional enrichment analysis of DEGs was performed using the DAVID tool. Then, the protein-protein international (PPI) network of these DEGs was visualized by Cytoscape, and the miRNA-target gene-disease regulatory networks were predicted using Webgestal. Results: A total of 18 common DEGs, 6 CD19-28z specific DEGs and 206 CD19-BBz specific DEGs were identified. Among CD19-28z specific DEGs, down-regulated PAX5 might be an important node in the PPI network and could be targeted by miR-496. In CD19-BBz group, JUN was a hub node in the PPI network and involved in the regulations of miR520D – early growth response gene 3 (EGR3)-JUN and mi-R489-AT-rich interaction domain 5A (ARID5A)-JUN networks. Conclusion: The 4-1BB co-stimulatory domain might play in important role in the treatment of CAR-T via miR-520D-EGR3-JUN and miR489-ARID5A-JUN regulation network, while CD28 had a negative effect on CAR-T treatment.

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Egr2 and Egr3 are the unique regulators for systemic autoimmunity

Cited by 18 publications

References 16 publications

Regulation of Vascular Smooth Muscle Cell Dysfunction Under Diabetic Conditions by miR-504

Regulation of Vascular Smooth Muscle Cell Dysfunction Under Diabetic Conditions by miR-504

Early Growth Response 3 (Egr3) Contributes a Maintenance of C2C12 Myoblast Proliferation

Chimeric Antigen Receptor-T Cells with 4-1BB Co-Stimulatory Domain Present a Superior Treatment Outcome than Those with CD28 Domain Based on Bioinformatics

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