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Cleavage of arrestin-3 by caspases attenuates cell death by precluding arrestin-dependent JNK activation.
Kook S, Vishnivetskiy SA, Gurevich VV, Gurevich EV
(2019) Cell Signal 54: 161-169
MeSH Terms: Animals, Apoptosis, Arrestins, COS Cells, Caspases, Chlorocebus aethiops, Etoposide, MAP Kinase Kinase 4, MAP Kinase Kinase Kinase 5
Show Abstract · Added March 18, 2020
The two non-visual subtypes, arrestin-2 and arrestin-3, are ubiquitously expressed and bind hundreds of G protein-coupled receptors. In addition, these arrestins also interact with dozens of non-receptor signaling proteins, including c-Src, ERK and JNK, that regulate cell death and survival. Arrestin-3 facilitates the activation of JNK family kinases, which are important players in the regulation of apoptosis. Here we show that arrestin-3 is specifically cleaved at Asp366, Asp405 and Asp406 by caspases during the apoptotic cell death. This results in the generation of one main cleavage product, arrestin-3-(1-366). The formation of this fragment occurs in a dose-dependent manner with the increase of fraction of apoptotic cells upon etoposide treatment. In contrast to a caspase-resistant mutant (D366/405/406E) the arrestin-3-(1-366) fragment reduces the apoptosis of etoposide-treated cells. We found that caspase cleavage did not affect the binding of the arrestin-3 to JNK3, but prevented facilitation of its activation, in contrast to the caspase-resistant mutant, which facilitated JNK activation similar to WT arrestin-3, likely due to decreased binding of the upstream kinases ASK1 and MKK4/7. The data suggest that caspase-generated arrestin-3-(1-366) prevents the signaling in the ASK1-MKK4/7-JNK1/2/3 cascade and protects cells, thereby suppressing apoptosis.
Copyright © 2018 Elsevier Inc. All rights reserved.
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9 MeSH Terms
Combining an Aurora Kinase Inhibitor and a Death Receptor Ligand/Agonist Antibody Triggers Apoptosis in Melanoma Cells and Prevents Tumor Growth in Preclinical Mouse Models.
Liu Y, Hawkins OE, Vilgelm AE, Pawlikowski JS, Ecsedy JA, Sosman JA, Kelley MC, Richmond A
(2015) Clin Cancer Res 21: 5338-48
MeSH Terms: Animals, Antibodies, Monoclonal, Antineoplastic Agents, Apoptosis, Aurora Kinases, Azepines, Caspases, Cell Line, Tumor, Cellular Senescence, Disease Models, Animal, Drug Evaluation, Preclinical, Female, Humans, Melanoma, Mice, Protein Kinase Inhibitors, Pyrimidines, Receptors, Death Domain, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor, Member 10c, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Show Abstract · Added August 21, 2015
PURPOSE - Preclinical studies show that inhibition of aurora kinases in melanoma tumors induces senescence and reduces tumor growth, but does not cause tumor regression. Additional preclinical models are needed to identify agents that will synergize with aurora kinase inhibitors to induce tumor regression.
EXPERIMENTAL DESIGN - We combined treatment with an aurora kinase A inhibitor, MLN8237, with agents that activate death receptors (Apo2L/TRAIL or death receptor 5 agonists) and monitored the ability of this treatment to induce tumor apoptosis and melanoma tumor regression using human cell lines and patient-derived xenograft (PDX) mouse models.
RESULTS - We found that this combined treatment led to apoptosis and markedly reduced cell viability. Mechanistic analysis showed that the induction of tumor cell senescence in response to the AURKA inhibitor resulted in a decreased display of Apo2L/TRAIL decoy receptors and increased display of one Apo2L/TRAIL receptor (death receptor 5), resulting in enhanced response to death receptor ligand/agonists. When death receptors were activated in senescent tumor cells, both intrinsic and extrinsic apoptotic pathways were induced independent of BRAF, NRAS, or p53 mutation status. Senescent tumor cells exhibited BID-mediated mitochondrial depolarization in response to Apo2L/TRAIL treatment. In addition, senescent tumor cells had a lower apoptotic threshold due to decreased XIAP and survivin expression. Melanoma tumor xenografts of one human cell line and one PDX displayed total blockage of tumor growth when treated with MLN8237 combined with DR5 agonist antibody.
CONCLUSIONS - These findings provide a strong rationale for combining senescence-inducing therapeutics with death receptor agonists for improved cancer treatment.
©2015 American Association for Cancer Research.
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24 MeSH Terms
Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium.
Chaum E, Winborn CS, Bhattacharya S
(2015) Mamm Genome 26: 210-21
MeSH Terms: Adult, Aged, 80 and over, Aging, Animals, Apoptosis, Caspases, Cell Line, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Gene Expression Regulation, Humans, Immunity, Innate, Interferon-alpha, Interferon-gamma, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Primary Cell Culture, Quantitative Trait Loci, Retinal Pigment Epithelium, Signal Transduction, Toll-Like Receptor 4, Tumor Suppressor Protein p53
Show Abstract · Added June 11, 2018
The tumor suppressor p53 is a major regulator of genes important for cell cycle arrest, senescence, apoptosis, and innate immunity, and has recently been implicated in retinal aging. In this study we sought to identify the genetic networks that regulate p53 function in the retina using quantitative trait locus (QTL) analysis. First we examined age-associated changes in the activation and expression levels of p53; known p53 target proteins and markers of innate immune system activation in primary retinal pigment epithelial (RPE) cells that were harvested from young and aged human donors. We observed increased expression of p53, activated caspase-1, CDKN1A, CDKN2A (p16INK4a), TLR4, and IFNα in aged primary RPE cell lines. We used the Hamilton Eye Institute (HEI) retinal dataset ( www.genenetwork.org ) to identify genomic loci that modulate expression of genes in the p53 pathway in recombinant inbred BXD mouse strains using a QTL systems biology-based approach. We identified a significant trans-QTL on chromosome 1 (region 172-177 Mb) that regulates the expression of Cdkn1a. Many of the genes in this QTL locus are involved in innate immune responses, including Fc receptors, interferon-inducible family genes, and formin 2. Importantly, we found an age-related increase in FCGR3A and FMN2 and a decrease in IFI16 levels in RPE cultures. There is a complex multigenic innate immunity locus that controls expression of genes in the p53 pathway in the RPE, which may play an important role in modulating age-related changes in the retina.
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MeSH Terms
Neuroprotective targets through which 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a sigma receptor ligand, mitigates the effects of methamphetamine in vitro.
Kaushal N, Robson MJ, Rosen A, McCurdy CR, Matsumoto RR
(2014) Eur J Pharmacol 724: 193-203
MeSH Terms: Animals, Apoptosis, Benzoxazoles, Caspases, Cell Line, Tumor, Fever, Ligands, Methamphetamine, Mice, Necrosis, Neuroprotective Agents, Piperazines, Reactive Nitrogen Species, Reactive Oxygen Species, Receptors, sigma, eIF-2 Kinase
Show Abstract · Added August 26, 2015
Exposure to high or repeated doses of methamphetamine can cause hyperthermia and neurotoxicity, which are thought to increase the risk of developing a variety of neurological conditions. Sigma receptor antagonism can prevent methamphetamine-induced hyperthermia and neurotoxicity, but the underlying cellular targets through which the neuroprotection is conveyed remain unknown. Differentiated NG108-15 cells were thus used as a model system to begin elucidating the neuroprotective mechanisms targeted by sigma receptor antagonists to mitigate the effects of methamphetamine. In differentiated NG108-15 cells, methamphetamine caused the generation of reactive oxygen/nitrogen species, an increase in PERK-mediated endoplasmic reticulum stress and the activation of caspase-3, -8 and -9, ultimately resulting in apoptosis at micromolar concentrations, and necrotic cell death at higher concentrations. The sigma receptor antagonist, 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), attenuated methamphetamine-induced increases in reactive oxygen/nitrogen species, activation of caspase-3, -8 and -9 and accompanying cellular toxicity. In contrast, 1,3-di(2-tolyl)-guanidine (DTG), a sigma receptor agonist, shifted the dose response curve of methamphetamine-induced cell death towards the left. To probe the effect of temperature on neurotoxicity, NG108-15 cells maintained at an elevated temperature (40 °C) exhibited a significant and synergistic increase in cell death in response to methamphetamine, compared to cells maintained at a normal cell culture temperature (37 °C). SN79 attenuated the enhanced cell death observed in the methamphetamine-treated cells at 40 °C. Together, the data demonstrate that SN79 reduces methamphetamine-induced reactive oxygen/nitrogen species generation and caspase activation, thereby conveying neuroprotective effects against methamphetamine under regular and elevated temperature conditions.
Copyright © 2014 Elsevier B.V. All rights reserved.
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16 MeSH Terms
Arrestins in apoptosis.
Kook S, Gurevich VV, Gurevich EV
(2014) Handb Exp Pharmacol 219: 309-39
MeSH Terms: Animals, Apoptosis, Arrestins, Caspases, DNA Damage, Endoplasmic Reticulum Stress, Humans, MAP Kinase Signaling System, Signal Transduction, Tumor Suppressor Protein p53, beta-Arrestins
Show Abstract · Added February 12, 2015
Programmed cell death (apoptosis) is a coordinated set of events eventually leading to the massive activation of specialized proteases (caspases) that cleave numerous substrates, orchestrating fairly uniform biochemical changes than culminate in cellular suicide. Apoptosis can be triggered by a variety of stimuli, from external signals or growth factor withdrawal to intracellular conditions, such as DNA damage or ER stress. Arrestins regulate many signaling cascades involved in life-or-death decisions in the cell, so it is hardly surprising that numerous reports document the effects of ubiquitous nonvisual arrestins on apoptosis under various conditions. Although these findings hardly constitute a coherent picture, with the same arrestin subtypes, sometimes via the same signaling pathways, reported to promote or inhibit cell death, this might reflect real differences in pro- and antiapoptotic signaling in different cells under a variety of conditions. Recent finding suggests that one of the nonvisual subtypes, arrestin-2, is specifically cleaved by caspases. Generated fragment actively participates in the core mechanism of apoptosis: it assists another product of caspase activity, tBID, in releasing cytochrome C from mitochondria. This is the point of no return in committing vertebrate cells to death, and the aspartate where caspases cleave arrestin-2 is evolutionary conserved in vertebrate, but not in invertebrate arrestins. In contrast to wild-type arrestin-2, its caspase-resistant mutant does not facilitate cell death.
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11 MeSH Terms
Palmitate-induced activation of mitochondrial metabolism promotes oxidative stress and apoptosis in H4IIEC3 rat hepatocytes.
Egnatchik RA, Leamy AK, Noguchi Y, Shiota M, Young JD
(2014) Metabolism 63: 283-95
MeSH Terms: Acetylcysteine, Animals, Antioxidants, Apoptosis, Carbon Isotopes, Carcinoma, Hepatocellular, Caspases, Effector, Cell Line, Tumor, Enzyme Activation, Hepatocytes, Liver Neoplasms, Metabolic Flux Analysis, Mitochondria, Liver, Oxidative Stress, Palmitates, Rats, Reactive Oxygen Species
Show Abstract · Added January 23, 2015
OBJECTIVE - Hepatic lipotoxicity is characterized by reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and excessive apoptosis, but the precise sequence of biochemical events leading to oxidative damage and cell death remains unclear. The goal of this study was to delineate the role of mitochondrial metabolism in mediating hepatocyte lipotoxicity.
MATERIALS/METHODS - We treated H4IIEC3 rat hepatoma cells with free fatty acids in combination with antioxidants and mitochondrial inhibitors designed to block key events in the progression toward apoptosis. We then applied (13)C metabolic flux analysis (MFA) to quantify mitochondrial pathway alterations associated with these treatments.
RESULTS - Treatment with palmitate alone led to a doubling in oxygen uptake rate and in most mitochondrial fluxes. Supplementing culture media with the antioxidant N-acetyl-cysteine (NAC) reduced ROS accumulation and caspase activation and partially restored cell viability. However, (13)C MFA revealed that treatment with NAC did not normalize palmitate-induced metabolic alterations, indicating that neither elevated ROS nor downstream apoptotic events contributed to mitochondrial activation. To directly limit mitochondrial metabolism, the complex I inhibitor phenformin was added to cells treated with palmitate. Phenformin addition eliminated abnormal ROS accumulation, prevented the appearance of apoptotic markers, and normalized mitochondrial carbon flow. Further studies revealed that glutamine provided the primary fuel for elevated mitochondrial metabolism in the presence of palmitate, rather than fatty acid beta-oxidation, and that glutamine consumption could be reduced through co-treatment with phenformin but not NAC.
CONCLUSION - Our results indicate that ROS accumulation in palmitate-treated H4IIEC3 cells occurs downstream of altered mitochondrial oxidative metabolism, which is independent of beta-oxidation and precedes apoptosis initiation.
© 2014.
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17 MeSH Terms
Caspase-cleaved arrestin-2 and BID cooperatively facilitate cytochrome C release and cell death.
Kook S, Zhan X, Cleghorn WM, Benovic JL, Gurevich VV, Gurevich EV
(2014) Cell Death Differ 21: 172-84
MeSH Terms: Animals, Apoptosis, Arrestins, BH3 Interacting Domain Death Agonist Protein, Caspase 3, Caspases, Cell Line, Cytochromes c, Etoposide, Mice, Mitochondria, Protein Binding, Protein Isoforms, Recombinant Proteins, Tumor Necrosis Factor-alpha
Show Abstract · Added February 12, 2015
Apoptosis is programmed cell death triggered by activation of death receptors or cellular stress. Activation of caspases is the hallmark of apoptosis. Arrestins are best known for their role in homologous desensitization of G protein-coupled receptors (GPCRs). Arrestins quench G protein activation by binding to activated phosphorylated GPCRs. Recently, arrestins have been shown to regulate multiple signalling pathways in G protein-independent manner via scaffolding signalling proteins. Here we demonstrate that arrestin-2 isoform is cleaved by caspases during apoptosis induced via death receptor activation or by DNA damage at evolutionarily conserved sites in the C-terminus. Caspase-generated arrestin-2-(1-380) fragment translocates to mitochondria increasing cytochrome C release, which is the key checkpoint in cell death. Cells lacking arrestin-2 are significantly more resistant to apoptosis. The expression of wild-type arrestin-2 or its cleavage product arrestin-2-(1-380), but not of its caspase-resistant mutant, restores cell sensitivity to apoptotic stimuli. Arrestin-2-(1-380) action depends on tBID: at physiological concentrations, arrestin-2-(1-380) directly binds tBID and doubles tBID-induced cytochrome C release from isolated mitochondria. Arrestin-2-(1-380) does not facilitate apoptosis in BID knockout cells, whereas its ability to increase caspase-3 activity and facilitate cytochrome C release is rescued when BID expression is restored. Thus, arrestin-2-(1-380) cooperates with another product of caspase activity, tBID, and their concerted action significantly contributes to cell death.
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15 MeSH Terms
Human embryonic stem cells: living on the edge.
Gama V, Deshmukh M
(2012) Cell Cycle 11: 3905-6
MeSH Terms: Apoptosis, Caspases, Cell Differentiation, Cytochromes c, DNA Damage, Embryonic Stem Cells, Golgi Apparatus, Humans, Mitochondria, bcl-2-Associated X Protein
Added October 26, 2015
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10 MeSH Terms
Resistance to TRAIL is mediated by DARPP-32 in gastric cancer.
Belkhiri A, Zhu S, Chen Z, Soutto M, El-Rifai W
(2012) Clin Cancer Res 18: 3889-900
MeSH Terms: Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein, Caspases, Cell Line, Tumor, Cell Transformation, Neoplastic, Dopamine and cAMP-Regulated Phosphoprotein 32, Gene Expression Regulation, Neoplastic, Humans, NF-kappa B, Signal Transduction, Stomach Neoplasms, TNF-Related Apoptosis-Inducing Ligand, bcl-X Protein
Show Abstract · Added September 3, 2013
PURPOSE - Dopamine and cAMP-regulated phosphoprotein, Mr 32,000 (DARPP-32), is overexpressed during the gastric carcinogenesis cascade. Here, we investigated the role of DARPP-32 in promoting resistance to treatment with TRAIL.
EXPERIMENTAL DESIGN - In vitro cell models including stable expression and knockdown of DARPP-32 were used. The role of DARPP-32 in regulating TRAIL-dependent apoptosis was evaluated by clonogenic survival assay, Annexin V staining, immunofluorescence, quantitative reverse transcriptase PCR, Western blot, and luciferase reporter assays.
RESULTS - Stable expression of DARPP-32 in MKN-28 cells enhanced cell survival and suppressed TRAIL-induced cytochrome c release and activation of caspase-8, -9, and -3. Conversely, short hairpin RNA-mediated knockdown of endogenous DARPP-32 sensitized the resistant MKN-45 cells to TRAIL-induced apoptosis and enhanced TRAIL-mediated activation of caspase-8, -9, and -3. DARPP-32 induced BCL-xL expression through activation of Src/STAT3 signaling, and treatment with the Src-specific inhibitor PP1 abrogated DARPP-32-dependent BCL-xL upregulation and cell survival in MKN-28 cells. The TRAIL treatment induced caspase-dependent cleavage of NF-κBp65 protein; this cleavage was prevented by DARPP-32, thus maintaining NF-κB activity and the expression of its target, FLIP(S) protein. This suggests that upregulation of BCL-xL could play a possible role in blocking the mitochondria intrinsic apoptosis pathway, whereas the DARPP-32 effect on the NF-κB/FLIP(S) axis could serve as an additional negative feedback loop that blocks TRAIL-induced activation of caspase-8.
CONCLUSION - Our findings uncover a novel mechanism of TRAIL resistance mediated by DARPP-32, whereby it inhibits the intrinsic apoptosis pathway through upregulation of BCL-xL, and the extrinsic apoptosis pathway through the NF-κB/FLIP(S) axis.
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13 MeSH Terms
Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor.
Wang L, Liu L, Shi Y, Cao H, Chaturvedi R, Calcutt MW, Hu T, Ren X, Wilson KT, Polk DB, Yan F
(2012) PLoS One 7: e36418
MeSH Terms: Active Transport, Cell Nucleus, Animals, Antineoplastic Agents, Apoptosis Inducing Factor, Berberine, Caspases, Cathepsin B, Cell Death, Cell Line, Tumor, Cell Nucleus, Colonic Neoplasms, Epithelial Cells, Humans, L-Lactate Dehydrogenase, Mice, Mitochondria, Poly(ADP-ribose) Polymerases, Reactive Oxygen Species
Show Abstract · Added March 5, 2014
Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apc(min) mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth.
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18 MeSH Terms