scholarly journals Secreted Cyclic Di-GMP Induces Stalk Cell Differentiation in the Eukaryote Dictyostelium discoideum

2015 ◽  
Vol 198 (1) ◽  
pp. 27-31 ◽  
Author(s):  
Zhi-hui Chen ◽  
Pauline Schaap
Keyword(s):  
Cell Death ◽  
Cell Differentiation ◽  
Dictyostelium Discoideum ◽  
Autophagic Cell Death ◽  
Stalk Cell ◽  
Signal Molecule ◽  
Major Life ◽  
Content Type

Cyclic di-GMP (c-di-GMP) is currently recognized as the most widely used intracellular signal molecule in prokaryotes, but roles in eukaryotes were only recently discovered. In the social amoebaDictyostelium discoideum, c-di-GMP, produced by a prokaryote-type diguanylate cyclase, induces the differentiation of stalk cells, thereby enabling the formation of spore-bearing fruiting bodies. In this review, we summarize the currently known mechanisms that control the major life cycle transitions ofDictyosteliumand focus particularly on the role of c-di-GMP in stalk formation. Stalk cell differentiation has characteristics of autophagic cell death, a process that also occurs in higher eukaryotes. We discuss the respective roles of c-di-GMP and of another signal molecule, differentiation-inducing factor 1, in autophagic cell deathin vitroand in stalk formationin vivo.

Induction by acid load of the maturation of prestalk cells in Dictyostelium discoideum

Development ◽  
1988 ◽  
Vol 104 (4) ◽  
pp. 669-681
Author(s):  
K. Inouye
Keyword(s):  
Cell Differentiation ◽  
Dictyostelium Discoideum ◽  
Cell Maturation ◽  
Stalk Cell ◽  
Body Construction ◽  
Acid Load ◽  
Cellular Slime ◽  
Plasma Membrane Proton Pump

During the process of fruiting body construction in the cellular slime mould Dictyostelium discoideum, prestalk cells become mature stalk cells in a well-controlled manner. To identify the natural inducer of stalk cell maturation, substances known to induce stalk cell differentiation under in vitro conditions, and some other related compounds, were examined for their effects in vivo on migrating slugs, the precursor structures of the fruiting bodies. Among these substances, addition of weak acids such as CO2, and addition followed by removal of weak bases such as NH3, strikingly induced the maturation of prestalk cells in situ in slugs. On the other hand, inhibitors of the plasma membrane proton pump did not efficiently induce the maturation of prestalk cells in intact slugs. Differentiation inducing factor (DIF), an endogenous inducer of prestalk differentiation, seemed to be an even poorer inducer of stalk cell maturation when applied to intact slugs. The activities of these substances in inducing stalk cell maturation showed a good correlation with their effects on the cytoplasmic pH (pHi) of prestalk cells; the larger the pHi drop, the stronger the induction of stalk cell maturation, suggesting a requirement for a pHi decrease for the maturation of prestalk cells. Based on these results, it was proposed that stalk cell differentiation, which is induced by DIF, is blocked halfway during normal development by (an) agent(s) that prevent(s) the decrease in pHi.

Ammonia depletion and DIF trigger stalk cell intact Dictyostelium discoideum slugs

Development ◽  
1989 ◽  
Vol 105 (3) ◽  
pp. 569-574 ◽  
Author(s):  
M. Wang ◽  
P. Schaap
Keyword(s):  
Cell Differentiation ◽  
Cyclic Amp ◽  
Dictyostelium Discoideum ◽  
Stalk Cell

The differentiation-inducing factor, DIF, was induce stalk cell differentiation in Dictyostelium incubated as submerged monolayers. We investigated the regulates the differentiation of stalk cells in the was found that in migrating or submerged slugs DIF cell differentiation, which is most likely due to the antagonist. Cyclic AMP and ammonia were earlier antagonists in vitro. We show here that ammonia, but an antagonist for DIF-induced stalk cell can induce stalk cell differentiation when ammonia are enzymically depleted. However, depletion of cAMP increase the efficacy of DIF. We propose that the cell differentiation during early culmination may be drop in ammonia levels inside the organism.

scholarly journals B Cell Activating Factor Inhibition Impairs Bacterial Immunity by Reducing T Cell-Independent IgM Secretion

2013 ◽  
Vol 81 (12) ◽  
pp. 4490-4497 ◽  
Author(s):  
Derek D. Jones ◽  
Maura Jones ◽  
Gregory A. DeIulio ◽  
Rachael Racine ◽  
Katherine C. MacNamara ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
B Cell ◽  
Host Defense ◽  
B Cell Differentiation ◽  
Content Type ◽  
Surface Marker Expression ◽  
B Cell Activating Factor

ABSTRACTB cell activating factor of the tumor necrosis factor family (BAFF) is an essential survival factor for B cells and has been shown to regulate T cell-independent (TI) IgM production. DuringEhrlichia murisinfection, TI IgM secretion in the spleen was BAFF dependent, and antibody-mediated BAFF neutralization led to an impairment of IgM-mediated host defense. The failure of TI plasmablasts to secrete IgM was not a consequence of alterations in their generation, survival, or early differentiation, since all occurred normally in infected mice following BAFF neutralization. Gene expression characteristic of plasma cell differentiation was also unaffected by BAFF neutralizationin vivo, and except for CD138, plasmablast cell surface marker expression was unaffected. IgM was produced, since it was detected intracellularly, and impaired secretion was not due to a failure to express the IgM secretory exon. Addition of BAFF to plasmablastsin vitrorescued IgM secretion, suggesting that BAFF signaling can directly regulate secretory processes. Our findings indicate that BAFF signaling can modulate TI host defense by acting at a late stage in B cell differentiation, via its regulation of terminal plasmablast differentiation and/or IgM secretion.

scholarly journals Targeting Positive Cofactor 4 induces autophagic cell death in MYC-expressing diffuse large B cell lymphoma

2021 ◽  
Author(s):  
Le Ma ◽  
Qiang Gong ◽  
Zelin Chen ◽  
Yu Wang ◽  
Xu Tan ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Autophagic Cell Death ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: The MYC-expressing diffuse large B-cell lymphoma (DLBCL) is one of the refractory lymphomas. The pathogenesis of MYC-expressing DLBCL is still unclear, and there is a lack of effective therapy. In this study, we have explored the clinical significance and the molecular mechanisms of transcription co-activator 4 (PC4) in MYC-expressing DLBCL.Methods: We investigated PC4 expression in 54 cases of DLBCL patients’ tissues and matched normal specimens, and studied the molecular mechanisms of PC4 in MYC-expressing DLBCL both in vitro and in vivo.Results: We reported for the first time that targeting c-Myc could induce autophagic cell death in MYC-expressing DLBCL cell lines. We next characterized that PC4 was an upstream regulator of c-Myc, and PC4 was overexpressed in DLBCL and was closely related to clinical staging, prognosis and c-Myc expression. Further, our in vivo and in vitro studies revealed that PC4 knockdown could induce autophagic cell death of MYC-expressing DLBCL. And inhibition of c-Myc mediated aerobic glycolysis and activation of AMPK / mTOR signaling pathway were responsible for the autophagic cell death induced by PC4 knockdown in MYC-expressing DLBCL. Through the CHIP, DLRTM and EMSA assay, we also found that PC4 exerted its oncogenic functions by directly binding to c-Myc promoters.Conclusions: PC4 exerts its oncogenic functions by directly binding to c-Myc promoters. Inhibition of PC4 can induce autophagic cell death of MYC-expressing DLBCL. Our study provides novel insights into the functions and mechanisms of PC4 in MYC-expressing DLBCL, and suggests that PC4 might be a promising therapeutic target for MYC-expressing DLBCL.

DUSP4 inhibits autophagic cell death in PTC by inhibiting JNK-BCL2-Beclin1 signaling

2021 ◽  
Author(s):  
Huixiang He ◽  
zhenshuang Du ◽  
Jianqing Lin ◽  
Wenyi Wu ◽  
Yihuang Yu
Keyword(s):  
Cell Death ◽  
Specific Inhibitor ◽  
Autophagic Cell Death ◽  
Negative Regulator ◽  
Loss Of Function ◽  
In Vivo Assays ◽  
Prevention And Cure ◽  
The Relationship

DUSP4 is a prognostic marker and potential target of papillary thyroid carcinoma (PTC). However, the molecular mechanism underlying DUSP4-regulated PTC carcinogenesis is unclear. DUSP4 is a negative regulator of the autophagy promoter, JNK. This study aimed to explore the relationship between DUSP4 and JNK-mediated autophagic cell death in PTC. In this study, we explored the roles of DUSP4 in PTC using gain-of-function and loss-of-function assays. In addition, we further identified the significance of JNK-BCL2-Beclin1-autophagy signaling on DUSP4-regulated PTC carcinogenesis by combining DUSP4 silencing with JNK specific inhibitor (SP600125). We found that DUSP4 silencing promoted the phosphorylation of JNK and BCL2 in PTC cells and enhanced the release of Beclin1 from BCL2-Beclin1 complex. DUSP4 silencing promoted autophagy and death in PTC cells.The death and autophagy enhanced by DUSP4 silencing was reversed by JNK inhibitor. We further extended the in vitro experiments by injecting K1 cells transduced with DUSP4-silencing vector subcutaneously into nude mice. In vivo assays showed that DUSP4 silencing not only inhibited tumor growth, but also promoted JNK and BCL2 phosphorylation and LC3II expression.Overall, DUSP4 inhibits BCL2-Beclin1- autophagy signaling through negatively regulating JNK activity, thus inhibiting PTC oncogenesis.This study provides more potential clues for the prevention and cure of PTC.

scholarly journals Molecular Characterization of anrsmD-Like rRNA Methyltransferase from the Wolbachia Endosymbiont of Brugia malayi and Antifilarial Activity of Specific Inhibitors of the Enzyme

2013 ◽  
Vol 57 (8) ◽  
pp. 3843-3856 ◽  
Author(s):  
Ajay Kumar Rana ◽  
Sharat Chandra ◽  
Mohammad Imran Siddiqi ◽  
Shailja Misra-Bhattacharya
Keyword(s):  
Significant Proportion ◽  
Intraperitoneal Administration ◽  
Brugia Malayi ◽  
Binding Mode ◽  
Cloning And Expression ◽  
Major Life ◽  
Content Type ◽  
Specific Inhibitors

ABSTRACTThe endosymbiotic organismWolbachiais an attractive antifilarial drug target. Here we report on the cloning and expression of anrsmD-like rRNA methyltransferase from theWolbachiaendosymbiont ofBrugia malayi, its molecular properties, and assays for specific inhibitors. The gene was found to be expressed in all the major life stages ofB. malayi. The purified enzyme expressed inEscherichia coliwas found to be in monomer form in its native state. The activities of the specific inhibitors (heteroaryl compounds) against the enzyme were tested withB. malayiadult and microfilariae for 7 daysin vitroat various concentrations, and NSC-659390 proved to be the most potent compound (50% inhibitory concentration [IC50], 0.32 μM), followed by NSC-658343 (IC50, 4.13 μM) and NSC-657589 (IC50, 7.5 μM). On intraperitoneal administration at 5 mg/kg of body weight for 7 days to adult jirds into whichB. malayihad been transplanted intraperitoneally, all the compounds killed a significant proportion of the implanted worms. A very similar result was observed in infected mastomys when inhibitors were administered. Docking studies of enzyme and inhibitors and anin vitrotryptophan quenching experiment were also performed to understand the binding mode and affinity. The specific inhibitors of the enzyme showed a higher affinity for the catalytic site of the enzyme than the nonspecific inhibitors and were found to be potent enough to kill the worm (both adults and microfilariae)in vitroas well asin vivoin a matter of days at micromolar concentrations. The findings suggest that these compounds be evaluated against other pathogens possessing a methyltransferase with a DPPY motif and warrant the design and synthesis of more such inhibitors.

scholarly journals CASK Silence Enhances Chemosensitivity of Hepatocellular Carcinoma Through activating Apoptosis, Inducing JNK/c-Jun-Mediated Autophagic Cell Death and Decreasing ABCG2

2021 ◽  
Author(s):  
BiSha Ding ◽  
Chang Bao ◽  
Luqi Jin ◽  
Liang Xu ◽  
Zhijun Dai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Autophagic Cell Death ◽  
Cell Counting ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment

Abstract Background: Advanced hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. Methods: The expression and prognostic role of calcium/calmodulin-dependent serine protein kinase (CASK) in HCC were assessed by combination of bioinformatic analysis and experimental validation. The effects of CASK in regulating proliferation, apoptosis and drug resistance of HCC cells in vitro and in vivo were investigated using gain- or loss-of-function strategies by performing lots of specific methods including Cell Counting kit-8 (CCK8), colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy and tumor xenograft experiments, immunohistochemistry staining. Moreover, the underlying molecular mechanisms responsible for CASK’s functions in HCC were also explored. Results: Currently, we discovered that CASK was positively associated with sorafenib resistance of HCC in vitro and in vivo, and was significantly related with poor prognosis in HCC. Moreover, inhibition of CASK can increase the effect of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite results. Besides, all the pan-caspase inhibitor Z-VAD-FMK, autophagy inhibitor 3-Methyladenine (3-MA) and small interfering RNA (siRNA) of LC3B reversed CASK knockout-induced effects with sorafenib treatment, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with si-JNK significantly attenuated CASK knockout-mediated autophagic cell death. Besides, knockout of CASK dramatically inhibited the expression of ATP binding cassette subfamily G member 2 (ABCG2) and reversed of multidrug-resistance (MDR) of HCC. Conclusions: Collectively, all these results together indicated that CASK might be a promising biomarker for HCC patients and a potential therapeutic target for relieving drug resistance of HCC.

Ophiopogonin D Attenuates Doxorubicin-Induced Autophagic Cell Death by Relieving Mitochondrial Damage In Vitro and In Vivo

2014 ◽  
Vol 352 (1) ◽  
pp. 166-174 ◽  
Author(s):  
Ying-Yu Zhang ◽  
Chen Meng ◽  
Xin-Mu Zhang ◽  
Cai-Hua Yuan ◽  
Ming-Da Wen ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Damage ◽  
Autophagic Cell Death

scholarly journals Fusobacterium nucleatum Promotes the Development of Ulcerative Colitis by Inducing the Autophagic Cell Death of Intestinal Epithelial

2020 ◽  
Vol 10 ◽  
Author(s):  
Wenhao Su ◽  
Yongyu Chen ◽  
Pan Cao ◽  
Yan Chen ◽  
Yuanmei Guo ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Cell Death ◽  
Epithelial Cell ◽  
Clinical Characteristics ◽  
Intestinal Epithelial Cell ◽  
Fusobacterium Nucleatum ◽  
Autophagic Cell Death ◽  
Intestinal Epithelial

There is a growing body of evidence which suggests that intestinal microbiota, especially Fusobacterium nucleatum (F. nucleatum), are associated with intestinal immune disease such as ulcerative colitis (UC). The mechanism by which F. nucleatum promotes intestinal epithelial cell (IEC) death remained undefined. Here, we investigated the potential mechanisms about how F. nucleatum aggravates IEC death in UC. We first detected the abundance of F. nucleatum in UC tissues and analyzed its relationship with the clinical characteristics of UC. Next, we explored whether F. nucleatum promotes intestinal epithelial cell death in vitro and in vivo. Furthermore, we extracted lipopolysaccharide (LPS) of the F. nucleatum and examined whether F. nucleatum exacerbates UC via LPS. Our results indicated that F. nucleatum was abundant in UC tissues and was correlated with clinical characteristics. In addition, we demonstrated that F. nucleatum and its LPS aggravated IEC death by promoted IEC autophagy. Furthermore, autophagy inhibitors, chloroquine (CQ), 3-methyladenine (3-MA) or Atg5 silencing prevented IEC death mediated by F. nucleatum, which suggests F. nucleatum may contribute to UC by activating autophagic cell death. All our results uncover a vital role of F. nucleatum in autophagic cell death and UC, giving rise to a new sight for UC therapy by inhibiting excessive IEC autophagy and autophagic cell death.

scholarly journals Bacteroides fragilis Strain ZY-312 Defense against Cronobacter sakazakii-Induced Necrotizing Enterocolitis In Vitro and in a Neonatal Rat Model

mSystems ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Hongying Fan ◽  
Zhenhui Chen ◽  
Ruqin Lin ◽  
Yangyang Liu ◽  
Xianbo Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Necrotizing Enterocolitis ◽  
Bacteroides Fragilis ◽  
Neonatal Rat ◽  
Cronobacter Sakazakii ◽  
Barrier Dysfunction ◽  
Content Type ◽  
Epithelial Barrier Dysfunction

ABSTRACT Cronobacter sakazakii is an important pathogen associated with the development of necrotizing enterocolitis (NEC), infant sepsis, and meningitis. Several randomized prospective clinical trials demonstrated that oral probiotics could decrease the incidence of NEC. Previously, we isolated and characterized a novel probiotic, Bacteroides fragilis strain ZY-312. However, it remains unclear how ZY-312 protects the host from the effects of C. sakazakii infection. To understand the underlying mechanisms triggering the probiotic effects, we tested the hypothesis that there was cross talk between probiotics/probiotics-modulated microbiota and the local immune system, governed by the permeability of the intestinal mucosa, using in vitro and in vivo models for the intestinal permeability. The probiotic effects of ZY-312 on intestinal epithelial cells were first examined, and the results revealed that ZY-312 inhibited C. sakazakii invasion, C. sakazakii-induced dual cell death (pyroptosis and apoptosis), and epithelial barrier dysfunction in vitro and in vivo. The presence of ZY-312 also resulted in decreased expression of an inflammasome (NOD-like receptor family member pyrin domain-containing protein 3 [NLRP3]), caspase-3, and serine protease caspase-1 in a neonatal rat model. Furthermore, ZY-312 significantly modulated the compositions of the intestinal bacterial communities and decreased the relative abundances of Proteobacteria and Gammaproteobacteria but increased the relative abundances of Bacteroides and Bacillus in neonatal rats. In conclusion, our findings have shown for the first time that the probiotic B. fragilis ZY-312 suppresses C. sakazakii-induced NEC by modulating the proinflammatory response and dual cell death (apoptosis and pyroptosis). IMPORTANCE Cronobacter sakazakii is an opportunistic pathogenic bacterium that can cause necrotizing enterocolitis (NEC). However, the mechanism of pathogenicity of C. sakazakii is largely unknown. Here we have now demonstrated that apoptotic and pyroptotic stimuli are effectors of C. sakazakii-induced NEC. Previously, we isolated a novel probiotic strain candidate from fecal samples from healthy infants and characterized it as Bacteroides fragilis strain ZY-312. Functional characterization reveals that ZY-312 inhibited C. sakazakii invasion, restoring epithelial barrier dysfunction, decreasing the expression of inflammatory cytokines, and reducing dual cell death (pyroptosis and apoptosis). Furthermore, the presence of ZY-132 was sufficient to hinder the adverse reaction seen with C. sakazakii in a C. sakazakii-induced NEC model. Taking the results together, our study demonstrated the utility of ZY-312 as a promising probiotic agent for the prevention of NEC.

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