scholarly journals p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes

2013 ◽  
Vol 201 (4) ◽  
pp. 613-629 ◽  
Author(s):  
Albert R. Davalos ◽  
Misako Kawahara ◽  
Gautam K. Malhotra ◽  
Nicholas Schaum ◽  
Jiahao Huang ◽  
...  
Keyword(s):  
Growth Arrest ◽  
High Mobility ◽  
Cytokine Secretion ◽  
Blocking Antibody ◽  
Extracellular Milieu ◽  
Hmgb1 Expression ◽  
Mouse Cells ◽  
Human And Mouse ◽  
Oncogenic Stress

Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation.

scholarly journals MiR-142-3p Overexpression Increases Chemo-Sensitivity of NSCLC by Inhibiting HMGB1-Mediated Autophagy

2017 ◽  
Vol 41 (4) ◽  
pp. 1370-1382 ◽  
Author(s):  
Yuqing Chen ◽  
Xin Zhou ◽  
Jianou Qiao ◽  
Aihua Bao
Keyword(s):  
Drug Resistance ◽  
Therapeutic Potential ◽  
High Mobility ◽  
In Silico Analysis ◽  
Luciferase Reporter ◽  
Hmgb1 Protein ◽  
Drug Induced ◽  
Hmgb1 Expression

Background: Non-small-cell lung cancer (NSCLC) is a deadly cancer with high mortality rate. Drug resistance represents a main obstacle in NSCLC treatment. High mobility group box-1 (HMGB1) protein promotes drug resistance in NSCLC cells by activating protective autophagy. Methods: In the current study, we investigated the regulatory role of microRNA-142-3p (miR-142-3p) in HMGB1-mediated autophagy of NSCLC cells and its impact on drug resistance of NSCLC in vitro and in vivo. HMGB1 was identified as a putative target gene of miR-142-3p by in silico analysis. Our luciferase reporter assay results confirmed that miR-142-3p directly targets the 3’-UTR of HMGB1 in NSCLC cells. Results: MiR-142-3p overexpression suppressed while miR-142-3p knockdown increased HMGB1 mRNA and protein expression. Starvation induced HMGB1 expression and activated autophagy in NSCLC cells. The starvation-induced autophagy was inhibited by miR-142-3p overexpression or HMGB1 knockdown. Moreover, miR-142-3p overexpression or HMGB1 knockdown increased PI3K, Akt, and mTOR phosphorylation. Inhibition of PI3K or mTOR restored starvation-induced autophagy inhibited by miR-142-3p overexpression or HMGB1 knockdown. Conclusions: These results demonstrated that miR-142-3p regulates starvation-induced autophagy of NSCLC cells by directly downregulating HMGB1 and subsequently activating the PI3K/Akt/mTOR pathway. Further, miR-142-3p overexpression inhibited anticancer drug-induced autophagy and increased chemo-sensitivity of NSCLC in vitro and in vivo. These findings shed light on the therapeutic potential of miR-142-3p in combating acquired NSCLC chemo-resistance.

scholarly journals Anti-HMGB1 Neutralizing Antibody Ameliorates Neutrophilic Airway Inflammation by Suppressing Dendritic Cell-Mediated Th17 Polarization

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Fang Zhang ◽  
Gang Huang ◽  
Bo Hu ◽  
Li-Ping Fang ◽  
E-Hong Cao ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Airway Inflammation ◽  
High Mobility ◽  
Neutralizing Antibody ◽  
Th17 Response ◽  
Neutrophilic Inflammation ◽  
Allergic Lung Inflammation ◽  
Hmgb1 Expression

We demonstrate that high mobility group box 1 protein (HMGB1) directs Th17 skewing by regulating dendritic cell (DC) function. First, ourin vitrostudies reveal that recombinant HMGB1 (rHMGB1) activates myeloid DCs to produce IL-23in vitro, and rHMGB1-activated DCs prime naïve lymphocytes to produce the Th17 cytokine IL-17A. Second, we demonstrate that anti-HMGB1 neutralizing antibody attenuates HMGB1 expression, neutrophilic inflammation, airway hyperresponsiveness, and Th17-related cytokine secretionin vivoby using a murine model of neutrophilic asthma induced by ovalbumin (OVA) plus lipopolysaccharide (LPS). Furthermore, anti-HMGB1 neutralizing antibody decreases the number of Th17 cells in lung cells and suppresses the production of IL-23 by lung CD11C+APCs. Finally, we show that intranasal adoptive transfer of rHMGB1-activated DCs was sufficient to restore lung neutrophilic inflammation and the Th17 response in a DC-driven model of asthma, whereas the transfer of rHMGB1 plus anti-HMGB1-treated mDCs significantly reduced these inflammation phenotypes. These data suggest, for the first time, that HMGB1 drives the DC-polarized Th17-type response in allergic lung inflammation and that blocking HMGB1 may benefit the attenuation of neutrophilic airway inflammation in asthma.

scholarly journals Ethyl Pyruvate Inhibits Retinal Pathogenic Neovascularization by Downregulating HMGB1 Expression

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yun Mi Lee ◽  
Junghyun Kim ◽  
Kyuhyung Jo ◽  
So Dam Shin ◽  
Chan-Sik Kim ◽  
...  
Keyword(s):  
Ethyl Pyruvate ◽  
High Mobility ◽  
Fluorescein Isothiocyanate ◽  
Causative Factor ◽  
Age Related Macular Degeneration ◽  
In Vivo Studies ◽  
Hmgb1 Protein ◽  
Age Related ◽  
Hmgb1 Expression

Retinal pathogenic angiogenesis in the eyes is a causative factor in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. This study was designed to examine the pathogenic role of the high-mobility group box-1 (HMGB1) protein and the inhibitory effect of ethyl pyruvate (EP), a well-known antioxidant substance, in retinal pathogenic angiogenesis in mice with oxygen-induced retinopathy (OIR), one of the animal models of proliferative ischemic retinopathy. The OIR mouse model was used for our in vivo studies. The mice were exposed to 75% oxygen from postnatal day 7 (P7) to P11, after which the mice were brought to room air and intraperitoneally injected with EP (50 mg/kg, or 100 mg/kg) for five days. At P17, the mice were perfused with fluorescein isothiocyanate-dextran, and flat-mounted retinas were used to measure nonperfused and neovascular tufts. In OIR mice, an intraperitoneal injection of EP reduced the nonperfused retinal area in the treatment group and significantly reduced the retinal neovascular tufts. In addition, EP inhibited the overexpression of HMGB1 in the retinas of OIR mice. These data suggest that EP could serve as an innovative pharmaceutical agent to prevent retinal neovascularization through inhibiting HMGB1 expression.

scholarly journals A 5S rRNA/L5 complex is a precursor to ribosome assembly in mammalian cells.

1988 ◽  
Vol 106 (3) ◽  
pp. 545-556 ◽  
Author(s):  
J A Steitz ◽  
C Berg ◽  
J P Hendrick ◽  
H La Branche-Chabot ◽  
A Metspalu ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
5S Rrna ◽  
5S Rna ◽  
Rna Molecules ◽  
La Protein ◽  
Rnp Complex ◽  
Mouse Cells ◽  
Protein Moiety ◽  
Human And Mouse

A novel 5S RNA-protein (RNP) complex in human and mouse cells has been analyzed using patient autoantibodies. The RNP is small (approximately 7S) and contains most of the nonribosome-associated 5S RNA molecules in HeLa cells. The 5S RNA in the particle is matured at its 3' end, consistent with the results of in vivo pulse-chase experiments which indicate that this RNP represents a later step in 5S biogenesis than a previously described 5S*/La protein complex. The protein moiety of the 5S RNP has been identified as ribosomal protein L5, which is known to be released from ribosomes in a complex with 5S after various treatments of the 60S subunit. Indirect immunofluorescence indicates that the L5/5S complex is concentrated in the nucleolus. L5 may therefore play a role in delivering 5S rRNA to the nucleolus for assembly into ribosomes.

scholarly journals Isolation and sequencing of AGO-bound RNAs reveals characteristics of mammalian stem-loop processing in vivo

2018 ◽  
Author(s):  
Ian M. Silverman ◽  
Sager J. Gosai ◽  
Nicholas Vrettos ◽  
Shawn W. Foley ◽  
Nathan D. Berkowitz ◽  
...  
Keyword(s):  
Mature Mirnas ◽  
Human Cells ◽  
Processing Efficiency ◽  
Stem Loop ◽  
Mature Micrornas ◽  
Mouse Cells ◽  
Low Levels ◽  
Short Hairpin Rnas ◽  
Human And Mouse

ABSTRACTMicroRNA precursors (pre-miRNAs) are short hairpin RNAs that are rapidly processed into mature microRNAs (miRNAs) in the cytoplasm. Due to their low abundance in cells, sequencing-based studies of pre-miRNAs have been limited. We successfully enriched for and deep sequenced pre-miRNAs in human cells by capturing these RNAs during their interaction with Argonaute (AGO) proteins. Using this approach, we detected > 350 pre-miRNAs in human cells and > 250 pre-miRNAs in a reanalysis of a similar study in mouse cells. We uncovered widespread trimming and non-templated additions to the 3’ ends of pre- and mature miRNAs. Additionally, we created an index for microRNA precursor processing efficiency. This analysis revealed a subset of pre-miRNAs that produce low levels of mature miRNAs despite abundant precursors, including an annotated miRNA in the 5’ UTR of the DiGeorge syndrome critical region 8 mRNA transcript. This led us to search for AGO-associated stem-loops originating from other mRNA species, which identified hundreds of putative pre-miRNAs derived from human and mouse mRNAs. In summary, we provide a wealth of information on mammalian pre-miRNAs, and identify novel microRNA and microRNA-like elements localized in mRNAs.

Replication of DNA containing apurinic sites in human and mouse cells probed with parvoviruses MVM and H-1

1987 ◽  
Vol 7 (7) ◽  
pp. 2620-2624
Author(s):  
J M Vos ◽  
J Rommelaere
Keyword(s):  
Mammalian Cells ◽  
Uv Light ◽  
Host Cells ◽  
Minute Virus Of Mice ◽  
Dna Viruses ◽  
Minute Virus ◽  
Mouse Cells ◽  
Viral Mutagenesis ◽  
Human And Mouse

We studied the effect of apurinic sites on DNA replication in mouse and human cells, using parvoviruses MVM (minute virus of mice) and H-1 as probes. Although apurinic sites are efficient blocks to the replication of these single-stranded DNA viruses in vivo, depurinated parvoviruses can be reactivated if host cells have been preexposed to a subtoxic dose of UV light. The target of this conditional reactivation process is the conversion of depurinated input DNA into double-stranded replicative forms; the concomitant increase in viral mutagenesis strongly suggests that apurinic sites can be bypassed in mammalian cells.

scholarly journals Development of an ObLiGaRe Doxycycline Inducible Cas9 system for pre-clinical cancer drug discovery

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Anders Lundin ◽  
Michelle J. Porritt ◽  
Himjyot Jaiswal ◽  
Frank Seeliger ◽  
Camilla Johansson ◽  
...  
Keyword(s):  
Gene Editing ◽  
Functional Integration ◽  
Cancer Drug ◽  
Cancer Drug Discovery ◽  
Mouse Cells ◽  
Genomic Editing ◽  
Human And Mouse ◽  
Mouse Genomic ◽  
In Cells

Abstract The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.

scholarly journals HMGB1 Localization during Experimental Periodontitis

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Andressa Vilas Boas Nogueira ◽  
João Antonio Chaves de Souza ◽  
Rafael Scaf de Molon ◽  
Elyne da Silva Mariano Pereira ◽  
Sabrina Garcia de Aquino ◽  
...  
Keyword(s):  
High Mobility ◽  
Tissue Destruction ◽  
Periodontal Ligament Fibroblasts ◽  
Pdl Cells ◽  
Inflammatory Stimuli ◽  
Hmgb1 Expression ◽  
Disease Induction ◽  
And Control

Aim.This study sought to investigate thein vitroexpression profile of high mobility group box 1 (HMGB1) in murine periodontal ligament fibroblasts (mPDL) stimulated with LPS or IL-1βandin vivoduring ligature- or LPS-induced periodontitis in rats.Material and Methods.For thein vivostudy, 36 rats were divided into experimental and control groups, and biopsies were harvested at 7–30 d following disease induction. Bone loss and inflammation were evaluated. HMGB1 expression was assessed by immunohistochemistry, qPCR, and Western blot.Results.Significant increases in mPDL HMGB1 mRNA occurred at 4, 8, and 12 h with protein expression elevated by 24 h. HMGB1 mRNA expression in gingival tissues was significantly increased at 15 d in the LPS-PD model and at 7 and 15 d in the ligature model. Immunohistochemical staining revealed a significant increase in the number of HMGB1-positive cells during the experimental periods.Conclusion.The results show that PDL cells produce HMGB1, which is increased and secreted extracellularly after inflammatory stimuli. In conclusion, this study demonstrates that HMGB1 may be associated with the onset and progression of periodontitis, suggesting that further studies should investigate the potential role of HMGB1 on periodontal tissue destruction.

scholarly journals The POU Transcription Factor Oct-1 Represses Virus-Induced Interferon A Gene Expression

2005 ◽  
Vol 25 (19) ◽  
pp. 8717-8731 ◽  
Author(s):  
Thibault Mesplède ◽  
Marie-Laure Island ◽  
Nicolas Christeff ◽  
Fahrettin Petek ◽  
Janine Doly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Infection ◽  
Regulatory Element ◽  
Adaptive Immune ◽  
Mouse Cells ◽  
Immune System Regulation ◽  
Human And Mouse ◽  
Control Of Expression

ABSTRACT Alpha interferon (IFN-α) and IFN-β are able to interfere with viral infection. They exert a vast array of biologic functions, including growth arrest, cell differentiation, and immune system regulation. This regulation extends from innate immunity to cellular and humoral adaptive immune responses. A strict control of expression is needed to prevent detrimental effects of unregulated IFN. Multiple IFN-A subtypes are coordinately induced in human and mouse cells infected by virus and exhibit differences in expression of their individual mRNAs. We demonstrated that the weakly expressed IFN-A11 gene is negatively regulated after viral infection, due to a distal negative regulatory element, binding homeoprotein pituitary homeobox 1 (Pitx1). Here we show that the POU protein Oct-1 binds in vitro and in vivo to the IFN-A11 promoter and represses IFN-A expression upon interferon regulatory factor overexpression. Furthermore, we show that Oct-1-deficient MEFs exhibit increased in vivo IFN-A gene expression and increased antiviral activity. Finally, the IFN-A expression pattern is modified in Oct-1-deficient MEFs. The broad representation of effective and potent octamer-like sequences within IFN-A promoters suggests an important role for Oct-1 in IFN-A regulation.

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