Chandipura virus requires pro-survival RelA NF-κB function for its propagation

SummaryIn response to infection by RNA viruses, mammalian cells typically activate RelA-containing NF-κB heterodimers, which induce genes encoding interferon-β and other antiviral mediators. Therefore, RelA is commonly thought to function as an anti-viral transcription factor. Notably, virus-specific mechanisms often modify mainstay immune pathways. Despite its human health relevance, how Chandipura virus (CHPV) per se interacts with the cellular signaling machinery has not been investigated. Here, we report that RelA deficiency abrogated antiviral gene expressions and yet surprisingly caused diminished growth of CHPV in mouse embryonic fibroblasts. Our experimental studies clarified that RelA-dependent synthesis of pro-survival factors restrained infection-inflicted cell death, and that exacerbated cell death processes prevented multiplication of CHPV in RelA-deficient cells. In sum, we identify a pro-viral function of the immune-activating transcription factor RelA NF-κB linked to its pro-survival properties.HighlightsLack of RelA NF-κB leads to reduced growth of CHPV ex vivoRelA deficiency exacerbates cell-death processes upon CHPV infectionInhibition of cell-death processes restores CHPV multiplication in RelA-deficient MEFs

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Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F.

Molecular and Cellular Biology ◽

10.1128/mcb.12.12.5620 ◽

1992 ◽

Vol 12 (12) ◽

pp. 5620-5631 ◽

Cited By ~ 159

Author(s):

B Shan ◽

X Zhu ◽

P L Chen ◽

T Durfee ◽

Y Yang ◽

...

Keyword(s):

Transcription Factor ◽

Mammalian Cells ◽

Leucine Zipper ◽

T Antigen ◽

Transactivation Domain ◽

Recognition Sequence ◽

Cellular Genes ◽

Genes Encoding ◽

Associated Proteins ◽

Transcription Factor E2f

The retinoblastoma protein interacts with a number of cellular proteins to form complexes which are probably crucial for its normal physiological function. To identify these proteins, we isolated nine distinct clones by direct screening of cDNA expression libraries using purified RB protein as a probe. One of these clones, Ap12, is expressed predominantly at the G1-S boundary and in the S phase of the cell cycle. The nucleotide sequence of Ap12 has features characteristic of transcription factors. The C-terminal region binds to unphosphorylated RB in regions similar to those to which T antigen binds and contains a transactivation domain. A region containing a potential leucine zipper flanked by basic residues is able to bind an E2F recognition sequence specifically. Expression of Ap12 in mammalian cells significantly enhances E2F-dependent transcriptional activity. These results suggest that Ap12 encodes a protein with properties known to be characteristic of transcription factor E2F.

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Syd/JIP3 Controls Tissue Size by Regulating Diap1 Protein Turnover Downstream of Yorkie/YAP

10.1101/2020.04.19.049023 ◽

2020 ◽

Author(s):

Vakil Ahmad ◽

Gangadhar P. Vadla ◽

Chiswili Y. Chabu

Keyword(s):

Cell Death ◽

Mammalian Cells ◽

De Novo ◽

Tissue Growth ◽

Organ Size ◽

List Type ◽

Wing Size ◽

Control Growth ◽

Control Organ ◽

Underlying Mechanisms

AbstractHow organisms control organ size is not fully understood. We found that Syd/JIP3 is required for proper wing size in Drosophila. JIP3 mutations are associated with organ size defects in mammals. The underlying mechanisms are not well understood. We discovered that Syd/JIP3 inhibition results in a downregulation of the inhibitor of apoptosis protein1 (Diap1) in the Drosophila wing. Correspondingly, Syd/JIP3 deficient tissues exhibit ectopic cell death and yield smaller wings. Syd/JIP3 inhibition generated similar effects in mammalian cells, indicating a conserved mechanism. We found that Yorkie/YAP stimulates Syd/JIP3 in Drosophila and mammalian cells. Notably, Syd/JIP3 is required for the full effect of Yorkie-mediated tissue growth. Thus Syd/JIP3 regulation of Diap1 functions downstream of Yorkie/YAP to control growth.This study provides mechanistic insights into the recent and perplexing link between JIP3 mutations and organ size defects in mammals, including in humans where de novo JIP3 variants are associated with microcephaly.HighlightsSyd/JIP3 is required for proper Drosophila wing sizeSyd/JIP3 stabilizes Diap1 to inhibit cell death in Drosophila and in mammalian cellsActivation of Yorkie/YAP stimulates Syd/JIP3Yorkie-mediated tissue growth is highly sensitive to Syd/JIP3 dosage

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In Vitro Effects of Sodium Benzoate on the Expression of T Cells-related Cytokines and Transcription Factors in Adjuvant-induced Arthritis Model

Iranian Journal of Allergy Asthma and Immunology ◽

10.18502/ijaai.v19i(s1.r1).2853 ◽

2020 ◽

Author(s):

Peyman Bemani ◽

Zahra Amirghofran ◽

Eskandar Kamali-Sarvestani

Keyword(s):

T Cells ◽

Transcription Factor ◽

Transcription Factors ◽

Sodium Benzoate ◽

Ex Vivo ◽

Disease Process ◽

Gene Expressions ◽

Adjuvant Induced Arthritis ◽

Ifn Γ

Though the exact etiology of rheumatoid arthritis (RA) is unknown, the contribution of immune cells in the disease process is completely acknowledged. T helper (Th) 1 and Th17-related cytokines are required for the disease development and progression, while Th2 and regulatory T cells (Tregs)-derived cytokines are protective. Studies have shown that sodium benzoate (NaB) can switch the balance of Th cell subsets toward Th2 and Tregs. The present study aimed to evaluate the possible effects of NaB on the expression of CD4+T cells-related cytokines and transcription factors in splenocytes derived from an animal model of RA, adjuvant-induced arthritis (AIA). AIA was induced in rats by injection of Freund's adjuvant containing mycobacterial antigens (Mtb). Splenocytes were isolated from AIA rats and restimulated ex vivo with Mtb in the presence or absence of NaB for 24 h. To determine the effects of NaB on the expression of T cells-related cytokine and transcription factor genes, real-time PCR was performed. NaB treatment of Mtb-stimulated splenocytes derived from arthritic rats resulted in significant increases in the gene expressions of Tregs-related cytokines (IL-10 and TGF-β) and Foxp3 transcription factor, and significant decreases in the expression of Th1-related cytokines (TNF-α and IFN-γ) and the T-bet transcription factor. The ratios of Th1/Th2 (IFN-γ/IL-4), Th1/Treg (IFN-γ/TGF-β and IFN-γ/IL-10) and Th17/Treg (IL-17/IL-10 and IL-17/IL-10+TGF-β)-related cytokines were also significantly decreased. In conclusion, NaB can potentially be considered as a useful therapeutic agent for the treatment of RA and other Th1 and Th17-mediated diseases.

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Activating transcription factor 3 is a negative regulator of allergic pulmonary inflammation

Journal of Experimental Medicine ◽

10.1084/jem.20072254 ◽

2008 ◽

Vol 205 (10) ◽

pp. 2349-2357 ◽

Cited By ~ 66

Author(s):

Mark Gilchrist ◽

William R. Henderson ◽

April E. Clark ◽

Randi M. Simmons ◽

Xin Ye ◽

...

Keyword(s):

Transcription Factor ◽

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Airway Disease ◽

Allergic Airway Disease ◽

Negative Regulator ◽

Activating Transcription Factor 3 ◽

Th2 Cytokine ◽

Genes Encoding ◽

Activating Transcription Factor

We recently demonstrated the pivotal role of the transcription factor (TF) activating TF 3 (ATF3) in dampening inflammation. We demonstrate that ATF3 also ameliorates allergen-induced airway inflammation and hyperresponsiveness in a mouse model of human asthma. ATF3 expression was increased in the lungs of mice challenged with ovalbumin allergen, and this was associated with its recruitment to the promoters of genes encoding Th2-associated cytokines. ATF3-deficient mice developed significantly increased airway hyperresponsiveness, pulmonary eosinophilia, and enhanced chemokine and Th2 cytokine responses in lung tissue and in lung-derived CD4+ lymphocytes. Although several TFs have been associated with enhanced inflammatory responses in the lung, ATF3 attenuates the inflammatory responses associated with allergic airway disease.

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Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response

Biochemical Journal ◽

10.1042/bj20020391 ◽

2002 ◽

Vol 366 (2) ◽

pp. 585-594 ◽

Cited By ~ 346

Author(s):

Tetsuya OKADA ◽

Hiderou YOSHIDA ◽

Rieko AKAZAWA ◽

Manabu NEGISHI ◽

Kazutoshi MORI

Keyword(s):

Endoplasmic Reticulum ◽

Transcription Factor ◽

Protein Kinase ◽

Er Stress ◽

Double Stranded Rna ◽

Unfolded Protein ◽

Genes Encoding ◽

Membrane Bound ◽

Activating Transcription Factor ◽

Protein Response

In response to accumulation of unfolded proteins in the endoplasmic reticulum (ER), a homoeostatic response, termed the unfolded protein response (UPR), is activated in all eukaryotic cells. The UPR involves only transcriptional regulation in yeast, and approx. 6% of all yeast genes, encoding not only proteins to augment the folding capacity in the ER, but also proteins working at various stages of secretion, are induced by ER stress [Travers, Patil, Wodicka, Lockhart, Weissman and Walter (2000) Cell (Cambridge, Mass.) 101, 249–258]. In the present study, we conducted microarray analysis of HeLa cells, although our analysis covered only a small fraction of the human genome. A great majority of human ER stress-inducible genes (approx. 1% of 1800 genes examined) were classified into two groups. One group consisted of genes encoding ER-resident molecular chaperones and folding enzymes, and these genes were directly regulated by the ER-membrane-bound transcription factor activating transcription factor (ATF) 6. The ER-membrane-bound protein kinase double-stranded RNA-activated protein kinase-like ER kinase (PERK)-mediated signalling pathway appeared to be responsible for induction of the remaining genes, which are not involved in secretion, but may be important after cellular recovery from ER stress. In higher eukaryotes, the PERK-mediated translational-attenuation system is known to operate in concert with the transcriptional-induction system. Thus we propose that mammalian cells have evolved a strategy to cope with ER stress different from that of yeast cells.

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Translational Paradigms in Cerebrovascular Gene Transfer

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000093324.07718.d4 ◽

2003 ◽

Vol 23 (11) ◽

pp. 1251-1262 ◽

Cited By ~ 10

Author(s):

Vini G Khurana ◽

Fredric B Meyer

Keyword(s):

Gene Transfer ◽

Blood Vessels ◽

Ex Vivo ◽

Present Report ◽

Cerebral Arteries ◽

Experimental Studies ◽

Gene Encoding ◽

Expression Of Genes ◽

Genes Encoding

Gene transfer involves the use of an engineered biologic vehicle known as a vector to introduce a gene encoding a protein of interest into a particular tissue. In diseases with known defects at a genetic level, gene transfer offers a potential means of restoring a normal molecular environment via vector-mediated entry (transduction) and expression of genes encoding potentially therapeutic proteins selectively in diseased tissues. The technology of gene transfer therefore underlies the concept of gene therapy and falls under the umbrella of the current genomics revolution. Particularly since 1995, numerous attempts have been made to introduce genes into intracranial blood vessels to demonstrate and characterize viable transduction. More recently, in attempting to translate cerebrovascular gene transfer technology closer to the clinical arena, successful transductions of normal human cerebral arteries ex vivo and diseased animal cerebral arteries in vivo have been reported using vasomodulatory vectors. Considering the emerging importance of gene-based strategies for the treatment of the spectrum of human disease, the goals of the present report are to overview the fundamentals of gene transfer and review experimental studies germane to the clinical translation of a technology that can facilitate genetic modification of cerebral blood vessels.

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Cardioprotection by the mitochondrial unfolded protein response (UPRmt) is mediated by activating transcription factor 5 (ATF5)

10.1101/344606 ◽

2018 ◽

Cited By ~ 1

Author(s):

Yves T. Wang ◽

Yunki Lim ◽

Matthew N. McCall ◽

Cole M. Haynes ◽

Keith Nehrke ◽

...

Keyword(s):

Transcription Factor ◽

Unfolded Protein Response ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Dependent Manner ◽

Nuclear Targeting ◽

Unfolded Protein ◽

Activating Transcription Factor ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

ABSTRACTThe mitochondrial unfolded protein response (UPRmt)1 is a cytoprotective signaling pathway triggered by mitochondrial dysfunction. Activation of the UPRmt upregulates nuclear-encoded mitochondrial genes, including those for chaperones, proteases, and antioxidants, as well as glycolysis, to restore proteostasis and cell energetics. Activating transcription factor 5 (ATF5), a protein with both mitochondrial and nuclear targeting sequences, is proposed to mediate mammalian UPRmt signaling. Since proteostasis and bioenergetics are important in the response of organs such as the heart to injury, we hypothesized that pharmacologic UPRmt activation may be cardioprotective against ischemia-reperfusion (IR) injury and that such protection would require ATF5. Using a perfused heart IR injury model in wild-type and global Atf5−/− mice, we found that in-vivo administration of the UPRmt inducers oligomycin or doxycycline 6 h prior to ex-vivo IR injury was cardioprotective. Such protection was absent in hearts from Atf5−/− mice, and no protection was observed with acute ex-vivo cardiac administration of doxycycline. Loss of ATF5 also did not alter baseline IR injury (without UPRmt induction). Cardiac gene expression analysis by RNA-Seq revealed mild induction of numerous genes in an ATF5-dependent manner, which may be important for cardioprotection. Analysis of hearts by qPCR showed that oligomycin at 6 h significantly induced genes encoding ATF5 and several known UPRmt-linked proteins. We conclude that ATF5 is required for cardioprotection induced by drugs that activate the UPRmt.

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Conserved epigenetic programming and enhanced heme metabolism drive memory B cell reactivation

10.1101/2021.01.20.427446 ◽

2021 ◽

Author(s):

Madeline J. Price ◽

Christopher D. Scharer ◽

Anna K. Kania ◽

Troy D. Randall ◽

Jeremy M. Boss

Keyword(s):

B Cells ◽

Plasma Cells ◽

Ex Vivo ◽

Chromatin Accessibility ◽

Memory B Cells ◽

List Type ◽

Differentiation Potential ◽

Altered Expression ◽

Genes Encoding ◽

Accessible Chromatin

ABSTRACTMemory B cells (MBCs) have enhanced capabilities to differentiate to plasma cells and generate a rapid burst of antibodies upon secondary stimulation. To determine if MBCs harbor an epigenetic landscape that contributes to increased differentiation potential, we derived the chromatin accessibility and transcriptomes of influenza-specific IgM and IgG MBCs compared to naïve cells. MBCs possessed an accessible chromatin architecture surrounding plasma cell specific genes, as well as altered expression of transcription factors and genes encoding cell cycle, chemotaxis, and signal transduction processes. Intriguingly, this MBC signature was conserved between humans and mice. MBCs of both species possessed a heightened heme signature compared to naïve cells. Differentiation in the presence of hemin enhanced oxidative phosphorylation metabolism and MBC differentiation into antibody secreting plasma cells. Thus, these data define conserved MBC transcriptional and epigenetic signatures that include a central role for heme and multiple other pathways in augmenting MBC reactivation potential.Key PointsInfluenza-specific memory B cells have accessible chromatin structure.Human and mouse memory B cells upregulate heme metabolic pathways.Heme enhances PC differentiation and augments mitochondrial metabolism in ex vivo.

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The Many Lives of Myc in the Pancreatic β-Cell

Journal of Biological Chemistry ◽

10.1074/jbc.rev120.011149 ◽

2020 ◽

pp. jbc.REV120.011149

Author(s):

Carolina Rosselot ◽

Sharon Baumel-Alterzon ◽

Yansui Li ◽

Gabriel Brill ◽

Luca Lambertini ◽

...

Keyword(s):

Cell Death ◽

Transcription Factor ◽

Therapeutic Potential ◽

Ex Vivo ◽

Diabetic Patients ◽

Cell Regeneration ◽

Diabetes Research ◽

Β Cells ◽

Β Cell

Diabetes results from insufficient numbers of functional pancreatic β-cells. Thus, increasing the number of available functional β-cells ex vivo for transplantation, or regenerating them in situ in diabetic patients, is a major focus of diabetes research. The transcription factor, Myc, discovered decades ago, lies at the nexus of most, if not all, known proliferative pathways. Based on this, many studies in the 1990’s and early 2000’s explored the potential of harnessing Myc expression to expand β-cells for diabetes treatment. Nearly all these studies in β-cells used pathophysiological or supraphysiological levels of Myc and reported enhanced β-cell death, de-differentiation or the formation of insulinomas if co-overexpressed with Bcl-xL, an inhibitor of apoptosis. This obviously reduced the enthusiasm for Myc as a therapeutic target for β-cell regeneration. However, recent studies indicate that “gentle” induction of Myc expression enhances β-cell replication without induction of cell death or loss of insulin secretion, suggesting that appropriate levels of Myc could have therapeutic potential for β-cell regeneration. Furthermore, although it has been known for decades that Myc is induced by glucose in β-cells very little is known about how this essential anabolic transcription factor perceives and responds to nutrients and increased insulin demand in vivo. Here we summarize the previous and recent knowledge of Myc in the β-cell, its potential for β-cell regeneration and its physiological importance for neonatal and adaptive β-cell expansion.

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