scholarly journals Bcl-3 Expression Promotes Cell Survival following Interleukin-4 Deprivation and Is Controlled by AP1 and AP1-Like Transcription Factors

2000 ◽  
Vol 20 (10) ◽  
pp. 3407-3416 ◽  
Author(s):  
Angelita Rebollo ◽  
Laure Dumoutier ◽  
Jean-Christophe Renauld ◽  
Angel Zaballos ◽  
Verónica Ayllón ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factors ◽  
Cell Survival ◽  
Binding Sites ◽  
Apoptotic Cell ◽  
Binding Activity ◽  
Interleukin 4 ◽  
Survival Factor ◽  
Induced Apoptosis

ABSTRACT We have analyzed the interleukin-4 (IL-4)-triggered mechanisms implicated in cell survival and show here that IL-4 deprivation induces apoptotic cell death but does not modulate Bcl-2 or Bcl-x expression. Since Bcl-x expression is insufficient to ensure cell survival in the absence of IL-4, we speculate that additional molecules replace the antiapoptotic role of Bcl-2 and Bcl-x in an alternative IL-4-triggered pathway. Cell death is associated with Bcl-3 downregulation and Bcl-3 expression blocks IL-4 deprivation-induced apoptosis, suggesting that Bcl-3 acts as a survival factor in the absence of growth factor. To characterize the IL-4-induced regulation of murine Bcl-3 expression, we cloned the promoter of this gene. Sequencing of the promoter showed no TATA box element but did reveal binding sites for AP1, AP1-like, and SP1 transcription factors. Retardation gels showed that IL-4 specifically induces AP1 and AP1-like binding activity and that mutation of these binding sites abolishes the IL-4-induced Bcl-3 promoter activity, suggesting that these transcription factors are important in Bcl-3 promoter transactivation. IL-4 deprivation induces downregulation of Jun expression and upregulation of Fos expression, both of which are proteins involved in the formation of AP1 and AP1-like transcription factors. Overexpression of Jun family proteins transactivates the promoter and restores Bcl-3 expression in the absence of IL-4 stimulation. Taken together, these data describe a new biological role for Bcl-3 and define the regulatory pathway implicated in Bcl-3 expression.

scholarly journals JNK1/2 regulates ER–mitochondrial Ca2+ cross-talk during IL-1β–mediated cell death in RINm5F and human primary β-cells

2013 ◽  
Vol 24 (12) ◽  
pp. 2058-2071 ◽  
Author(s):  
Gaurav Verma ◽  
Himanshi Bhatia ◽  
Malabika Datta
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Mitochondrial Permeability Transition ◽  
Apoptotic Cell ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Β Cells ◽  
Mediating Role ◽  
Induced Apoptosis

Elevated interleukin-1β (IL-1β) induces apoptosis in pancreatic β-cells through endoplasmic reticulum (ER) stress induction and subsequent c-jun-N-terminal kinase 1/2 (JNK1/2) activation. In earlier work we showed that JNK1/2 activation is initiated before ER stress and apoptotic induction in response to IL-1β. However, the detailed regulatory mechanisms are not completely understood. Because the ER is the organelle responsible for Ca2+ handling and storage, here we examine the effects of IL-1β on cellular Ca2+ movement and mitochondrial dysfunction and evaluate the role of JNK1/2. Our results show that in RINm5F cells and human primary β-cells, IL-1β alters mitochondrial membrane potential, mitochondrial permeability transition pore opening, ATP content, and reactive oxygen species production and these alterations are preceded by ER Ca2+ release via IP3R channels and mitochondrial Ca2+ uptake. All these events are prevented by JNK1/2 small interfering RNA (siRNA), indicating the mediating role of JNK1/2 in IL-1β–induced cellular alteration. This is accompanied by IL-1β–induced apoptosis, which is prevented by JNK1/2 siRNA and the IP3R inhibitor xestospongin C. This suggests a regulatory role of JNK1/2 in modulating the ER-mitochondrial-Ca2+ axis by IL-1β in apoptotic cell death.

A Novel Sphingomyelin Synthase Gene, SMS1-Regulated Sphingomyelin/Ceramide-Rich Microdomain Plays a Crucial Role in Fas-Mediated Apoptosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1266-1266
Author(s):  
Michihiko Miyaji ◽  
Shohei Yamaoka ◽  
Jin Zhe Xiong ◽  
Ryuichi Amakawa ◽  
Tsuneyo Mimori ◽  
...  
Keyword(s):  
Cell Death ◽  
Crucial Role ◽  
Apoptotic Cell ◽  
Cholesterol Content ◽  
Sphingomyelin Synthase ◽  
Microscopy Analysis ◽  
Induced Apoptosis ◽  
Lipid Microdomain ◽  
First Time

Abstract Lipid microdomain consisting of sphingolipids, glycosphingolipids and cholesterol plays an important role in mediating cell death signals. Although functional analysis of lipid microdomain is conventionally performed by exclusion of cholesterol tightly binding with sphingomyein (SM), the exact role of SM in microdomain in signal transduction remains to be cleared. Since we for the first time obtained cDNA (SMS1) responsible for SM synthesis, it became possible to investigate the role of SM in the membrane without affecting cholesterol content. We here examine the role of SM/ceramide-rich microdomain in Fas-induced apoptosis using the SM-deficient cells and its revertant cells by transfection with SMS1. SM synthase-defective WR19L cells transfected with human-Fas gene (WR/Fas-SM(-)), and its functional revertant cells by transfection with SMS1 (WR/Fas-SMS1) were established. Both SMS1 cells and SM(-) cells expressed similar levels of CD44, CD90, CD95 (Human) and LFA-1 by FACS analysis. Although the levels of cholesterol and GM1-ganglioside on the surface of the membrane were similar in both cells, SM was detected only on the surface of SMS1 cells by FACS and confocal microscopy analysis. Fas crosslinking induced not only higher rate of apoptotic cell death, but also translocation of Fas into TritonX-100-insoluble fractions with a significant increase of ceramide in SMS1 cells as compared with SM(-) cells. After increase of SM and ceramide in microdomain, more efficient aggregation of Fas was detected with increase of DISC formation, resulting in activation of caspase-8 and 3 and decrease of mitochondrial membrane potential in SMS-1 cells than SM(-) cells. Our results clearly demonstrate that SM and ceramide in microdomain of plasma membrane plays a crucial role in Fas clustering and aggregation requires for activation of apoptosis-inducing signals.

NF-κB activation and susceptibility to apoptosis after polyamine depletion in intestinal epithelial cells

2001 ◽  
Vol 280 (5) ◽  
pp. G992-G1004 ◽  
Author(s):  
Li Li ◽  
Jaladanki N. Rao ◽  
Barbara L. Bass ◽  
Jian-Ying Wang
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Nuclear Translocation ◽  
Intestinal Epithelial Cells ◽  
Apoptotic Cell ◽  
Binding Activity ◽  
Cell Renewal ◽  
Intestinal Epithelial ◽  
Tnf Α ◽  
Induced Apoptosis

The maintenance of intestinal mucosal integrity depends on a balance between cell renewal and cell death, including apoptosis. The natural polyamines, putrescine, spermidine, and spermine, are essential for mucosal growth, and decreasing polyamine levels cause G1 phase growth arrest in intestinal epithelial (IEC-6) cells. The present study was done to determine changes in susceptibility of IEC-6 cells to apoptosis after depletion of cellular polyamines and to further elucidate the role of nuclear factor-κB (NF-κB) in this process. Although depletion of polyamines by α-difluoromethylornithine (DFMO) did not directly induce apoptosis, the susceptibility of polyamine-deficient cells to staurosporine (STS)-induced apoptosis increased significantly as measured by changes in morphological features and internucleosomal DNA fragmentation. In contrast, polyamine depletion by DFMO promoted resistance to apoptotic cell death induced by the combination of tumor necrosis factor-α (TNF-α) and cycloheximide. Depletion of cellular polyamines also increased the basal level of NF-κB proteins, induced NF-κB nuclear translocation, and activated the sequence-specific DNA binding activity. Inhibition of NF-κB binding activity by sulfasalazine or MG-132 not only prevented the increased susceptibility to STS-induced apoptosis but also blocked the resistance to cell death induced by TNF-α in combination with cycloheximide in polyamine-deficient cells. These results indicate that 1) polyamine depletion sensitizes intestinal epithelial cells to STS-induced apoptosis but promotes the resistance to TNF-α-induced cell death, 2) polyamine depletion induces NF-κB activation, and 3) disruption of NF-κB function is associated with altered susceptibility to apoptosis induced by STS or TNF-α. These findings suggest that increased NF-κB activity after polyamine depletion has a proapoptotic or antiapoptotic effect on intestinal epithelial cells determined by the nature of the death stimulus.

scholarly journals Oxidized LDL Suppresses NF-κB and Overcomes Protection from Apoptosis in Activated Endothelial Cells

2001 ◽  
Vol 12 (3) ◽  
pp. 456-463
Author(s):  
KATHRIN HEERMEIER ◽  
WOLFGANG LEICHT ◽  
ALOIS PALMETSHOFER ◽  
MARKUS ULLRICH ◽  
CHRISTOPH WANNER ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Cell Survival ◽  
Apoptotic Cell ◽  
Oxidized Ldl ◽  
Density Lipoprotein ◽  
Nuclear Factor Κb ◽  
Chronic Inflammatory Disease ◽  
Tnf Α ◽  
Induced Apoptosis

Abstract. Atherosclerosis is a chronic inflammatory disease associated with enhanced apoptotic cell death in vascular cells, partly induced by oxidized low-density lipoprotein (OxLDL). However, proinflammatory stimuli such as lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α) activate endothelial cells (EC) and inhibit apoptosis through induction of nuclear factor κB (NF-κB)-dependent genes. This study therefore investigated whether OxLDL or its component, lysophosphatidylcholine (LPC), interacts with the effect of LPS or TNF-α on cell survival. Human EC were incubated with LPS, TNF-α, OxLDL, or LPC alone or in combinations. OxLDL (100 to 200 μg/ml) and LPC (100 to 300 μM) induced apoptosis dose-dependently. LPS and TNF-α had no effect on cell survival in the presence or absence of OxLDL or LPC. LPS and TNF-α both induced the antiapoptotic gene A20, whereas OxLDL and LPC suppressed its induction. Expression of A20 is regulated by NF-κB. OxLDL and LPC dose-dependently suppressed NF-κB activity. For functional analysis, bovine EC were transfected with A20 encoding expression constructs in sense and antisense orientation. Bovine EC that overexpressed A20 were protected against OxLDL-induced apoptosis, whereas expression of antisense A20 rendered cells more sensitive to OxLDL. These results suggest that OxLDL not only induces cell death, as has been shown before, but also compromises antiapoptotic protection of activated EC. OxLDL sensitizes EC to apoptotic triggers by interfering with the induction of A20 during the inflammatory response seen in atherosclerotic lesions. This inhibition is based on repression of NF-κB activation. The effect may be caused by the OxLDL component LPC.

scholarly journals Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic Conditions

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4027
Author(s):  
Alibek Abdrakhmanov ◽  
Maria A. Yapryntseva ◽  
Vitaliy O. Kaminskyy ◽  
Boris Zhivotovsky ◽  
Vladimir Gogvadze
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
A549 Cells ◽  
Inhibitory Effect ◽  
Protective Role ◽  
Hypoxic Conditions ◽  
Key Enzyme ◽  
Induced Apoptosis ◽  
Key Participants

Targeting mitochondria with thenoyltrifluoroacetone (TTFA), an inhibitor of Complex II in the respiratory chain, stimulated cisplatin-induced apoptosis in various cell lines in normoxia but not in hypoxia. This can be explained by the elimination of mitochondria involved in triggering apoptotic cell death by mitophagy, either Parkin-dependent or receptor-mediated. Treatment with TTFA alone or in combination with cisplatin did not cause accumulation of PINK1, meaning that under hypoxic conditions cells survive through activation of a receptor-mediated pathway. Hypoxia triggers the accumulation of BNIP3 and BNIP3L (also known as NIX), key participants in receptor-mediated mitophagy. Under hypoxic conditions, stimulation of autophagy, as assessed by the accumulation of lipidated form of LC3 (LC3II), was observed. To exclude the contribution of canonical macroautophagy in LC3II accumulation, experiments were performed using U1810 cells lacking ATG13, a key enzyme of macroautophagy. Despite the absence of ATG13, hypoxia-mediated accumulation of LC3II was not affected, underlying the importance of the receptor-mediated pathway. In order to prove the protective role of BNIP3 against cisplatin-induced apoptosis, BNIP3-deficient A549 cells were used. Surprisingly, a BNIP3 knockout did not abolish hypoxia-induced protection; however, in cells lacking BNIP3, a compensatory upregulation of BNIP3L was detected. Thus, in the absence of BNIP3, mitophagy could be maintained by BNIP3L and lead to cell death suppression due to the elimination of proapoptotic mitochondria. When both BNIP3 and BNIP3L were knocked out, the inhibitory effect of hypoxia on apoptosis was diminished, although not abolished completely. Undoubtedly, receptor-mediated mitophagy is likely to be one of the mechanisms responsible for cell death suppression under hypoxic conditions.

Modulation of LPS-induced Cell Death by 5,6,7,8-Tetrahydrobiopterin

Pteridines ◽  
1999 ◽  
Vol 10 (4) ◽  
pp. 202-206
Author(s):  
Hiroyuki Iizuka ◽  
Hirofumi Sagara ◽  
Shuji Kojima
Keyword(s):  
Cell Death ◽  
Antioxidative Activity ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Nitrate Content ◽  
Oxygen Species ◽  
No Donor ◽  
Induced Apoptosis ◽  
Raw 264.7 Cell Line

SummaryIt has been previously reported that 5,6,7,S-tetrahydrobiopterin (BH4) modulates HL-60 cell death induced by a nitric oxide (NO) donor, S-nitroso-N-acetyl-D, L-penicillamine (SNAP). In this study, the role of endogenous BH4 was investigated in lipopolysaccharide (LPS)-induced apoptotic cell death. LPS induced an increase of DNA fragmentation and of nitrite and nitrate content (NOx content) in the macrophage- like RAW 264.7 cell line. 2,4-Diamino-6-hydroxypyrimidine (DAHP) , an inhibitor of BH4 synthesis, suppressed both of them. The NOx content of cells treated with LPS and interferon-y was much higher than that of cells treated with LPS alone. However, the degree of apoptotic cell death induced by LPS and interferon-y did not differ significantly from that induced by LPS alone. Further investigation revealed that LPS-induced cell death of RAW264.7 cells was mainly mediated by reactive oxygen species, such as hydrogen peroxide (H2O2). From these data, it was speculated that BH4 might be a modulator in NO-induced apoptosis, in which BH4 involves LPS-induced cell death by its function asa cofactor of inducible NO synthase and it suppresses the cell death mediated by NO and/or H2O2 via an antioxidative activity.

scholarly journals Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 365
Author(s):  
Carina Colturato-Kido ◽  
Rayssa M. Lopes ◽  
Hyllana C. D. Medeiros ◽  
Claudia A. Costa ◽  
Laura F. L. Prado-Souza ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clinical Problem ◽  
Jurkat Cells ◽  
Leukemia Cells ◽  
Peripheral Mononuclear Blood ◽  
Induced Apoptosis ◽  
Cure Rates

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a “double-edged sword” contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL.

scholarly journals Pancreatic islet cell survival following islet isolation: the role of cellular interactions in the pancreas

1999 ◽  
Vol 161 (3) ◽  
pp. 357-364 ◽  
Author(s):  
A Ilieva ◽  
S Yuan ◽  
RN Wang ◽  
D Agapitos ◽  
DJ Hill ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Islet Cell ◽  
Apoptotic Cell ◽  
Specific Cell ◽  
Cellular Interactions ◽  
Pancreatic Islet Cell ◽  
Beneficial Result ◽  
Trophic Effect ◽  
Ductal Epithelium

The purpose of this study was to characterize the trophic effect of pancreatic duct cells on the islets of Langerhans. Ductal epithelium and islets were isolated from hamster pancreata. In addition, duct-conditioned medium (DCM) was prepared from primary duct cultures that had been passaged twice to remove other cellular elements. Three experimental groups were then established: Group 1, 100 islets alone; Group 2, 100 islets+80 duct fragments; and Group 3, 100 islets in 25% DCM. All tissues were embedded in rat tail collagen for up to 12 days and the influence of pancreatic ductal epithelium on islet cell survival was examined. By day 12, 20.6+/-3. 0% (S.E.M.) of the islets cultured alone developed central necrosis, compared with 6.7+/-2.0% of the islets co-cultured with ducts and 5.6+/-1.5% of the islets cultured in DCM (P<0.05). The presence of apoptotic cell death was determined by a TdT-mediated dUTP-biotin nick end labelling (TUNEL) assay and by a specific cell death ELISA. DNA fragmentation in islets cultured alone was significantly increased compared with islets cultured either in the presence of duct epithelium or in DCM (P<0.05). More than 80% of TUNEL-positive cells were situated in the inner 80% of the islet area, suggesting that most were beta-cells. DCM was analysed for known growth factors. The presence of a large amount of IGF-II (34 ng/ml) and a much smaller quantity of nerve growth factor (4 ng/ml) was identified. When the apoptosis studies were repeated to compare islets alone, islets+DCM and islets+IGF-II, the cell death ELISA indicated that IGF-II produced the same beneficial result as DCM when compared with islets cultured alone. We conclude that pancreatic ductal epithelium promotes islet cell survival. This effect appears to be mediated in a paracrine manner by the release of IGF-II from cells in the ductal epithelium.

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