22 results on '"Ostrakhovitch, Elena A."'
Search Results
2. A H2S-Nampt dependent energetic circuit is critical to survival and cytoprotection from damage in cancer cells.
- Author
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Sanokawa-Akakura, Reiko, Ostrakhovitch, Elena A, Akakura, Shin, Goodwin, Scott, and Tabibzadeh, Siamak
- Subjects
Cell Line ,Tumor ,Animals ,Humans ,Mice ,Mice ,Nude ,Melanoma ,Carcinoma ,Hepatocellular ,Liver Neoplasms ,Hydrogen Sulfide ,Hydrogen Peroxide ,Acrylamides ,Piperidines ,Neoplasm Proteins ,Adenosine Triphosphate ,Cytokines ,Cell Hypoxia ,Cell Survival ,Aerobiosis ,Energy Metabolism ,Glycolysis ,Male ,Nicotinamide Phosphoribosyltransferase ,Triple Negative Breast Neoplasms ,General Science & Technology - Abstract
We recently demonstrated that cancer cells that recover from damage exhibit increased aerobic glycolysis, however, the molecular mechanism by which cancer cells survive the damage and show increased aerobic glycolysis remains unknown. Here, we demonstrate that diverse cancer cells that survive hypoxic or oxidative damage show rapid cell proliferation, and develop tolerance to damage associated with increased production of hydrogen sulfide (H2S) which drives up-regulation of nicotinamide phosphoribosyltransferase (Nampt). Consistent with existence of a H2S-Nampt energetic circuit, in damage recovered cancer cells, H2S, Nampt and ATP production exhibit a significant correlation. Moreover, the treatment of cancer cells with H2S donor, NaHS, coordinately increases Nampt and ATP levels, and protects cells from drug induced damage. Inhibition of cystathionine beta synthase (CBS) or cystathionase (CTH), enzymes which drive generation of H2S, decreases Nampt production while suppression of Nampt pathway by FK866, decreases H2S and ATP levels. Damage recovered cells isolated from tumors grown subcutaneously in athymic mice also show increased production of H2S, Nampt and ATP levels, associated with increased glycolysis and rapid proliferation. Together, these data show that upon recovery from potential lethal damage, H2S-Nampt directs energy expenditure and aerobic glycolysis in cancer cells, leads to their exponential growth, and causes a high degree of tolerance to damage. Identification of H2S-Nampt as a pathway responsible for induction of damage tolerance in cancer cells may underlie resistance to therapy and offers the opportunity to target this pathway as a means in treatment of cancer.
- Published
- 2014
3. Dedifferentiation of cancer cells following recovery from a potentially lethal damage is mediated by H2S–Nampt
- Author
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Ostrakhovitch, Elena A., Akakura, Shin, Sanokawa-Akakura, Reiko, Goodwin, Scott, and Tabibzadeh, Siamak
- Published
- 2015
- Full Text
- View/download PDF
4. NIP1/DUOXA1 expression in epithelial breast cancer cells: regulation of cell adhesion and actin dynamics
- Author
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Ostrakhovitch, Elena A. and Li, Shawn S. C.
- Published
- 2010
- Full Text
- View/download PDF
5. The role of SLAM family receptors in immune cell signaling (1)
- Author
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Ostrakhovitch, Elena A. and Li, Shawn S.-C.
- Subjects
Immune system -- Research ,Lymphocytes -- Properties -- Research ,Cellular signal transduction -- Research ,Cell receptors -- Properties -- Influence -- Research ,Biological sciences ,Influence ,Research ,Properties - Abstract
Abstract: The signaling lymphocyte-activating molecule (SLAM) family immunoreceptors are expressed in a wide array of immune cells, including both T and B lymphocytes. By virtue of their ability to transduce [...]
- Published
- 2006
6. Hydrogen sulfide facilitates reprogramming and trans-differentiation in 3D dermal fibroblast.
- Author
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Ostrakhovitch, Elena A., Akakura, Shin, and Tabibzadeh, Siamak
- Subjects
- *
HYDROGEN sulfide , *LACTIC acid , *GENE expression , *CELL culture , *PRODUCTION increases , *CELL aggregation - Abstract
The efficiency of cell reprogramming in two-dimensional (2D) cultures is limited. Given that cellular stemness is intimately related to microenvironmental changes, 3D cell cultures have the potential of overcoming this limited capacity by allowing cells to self-organize by aggregation. In 3D space, cells interact more efficiently, modify their cellular topology, gene expression, signaling, and metabolism. It is yet not clear as how 3D culture environments modify the reprogramming potential of fibroblasts. We demonstrate that 3D spheroids from dermal fibroblasts formed under ultra-low attachment conditions showed increased lactate production. This is a requisite for cell reprogramming, increase their expression of pluripotency genes, such as OCT4, NANOG and SOX2, and display upregulated cystathionine-β-synthase (CBS) and hydrogen sulfide (H2S) production. Knockdown of CBS by RNAi suppresses lactic acid and H2S production and concomitantly decreases the expression of OCT4 and NANOG. On the contrary, H2S donors, NaHS and garlic-derived diallyl trisulfide (DATS), promote the expression of OCT4, and support osteogenic trans-differentiation of fibroblasts. These results demonstrate that CBS mediated release of H2S regulates the reprogramming of dermal fibroblasts grown in 3D cultures and supports their trans-differentiation. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
7. Interaction of metallothionein with tumor suppressor p53 protein
- Author
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Ostrakhovitch, Elena A., Olsson, Per-Erik, Jiang, Sean, and Cherian, M. George
- Published
- 2006
- Full Text
- View/download PDF
8. A H2S-Nampt Dependent Energetic Circuit Is Critical to Survival and Cytoprotection from Damage in Cancer Cells.
- Author
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Sanokawa-Akakura, Reiko, Ostrakhovitch, Elena A., Akakura, Shin, Goodwin, Scott, and Tabibzadeh, Siamak
- Subjects
- *
CANCER cells , *CYTOPROTECTION , *GLYCOLYSIS , *OXIDATIVE stress , *PHOSPHORIBOSYLTRANSFERASES , *BIOENERGETICS - Abstract
We recently demonstrated that cancer cells that recover from damage exhibit increased aerobic glycolysis, however, the molecular mechanism by which cancer cells survive the damage and show increased aerobic glycolysis remains unknown. Here, we demonstrate that diverse cancer cells that survive hypoxic or oxidative damage show rapid cell proliferation, and develop tolerance to damage associated with increased production of hydrogen sulfide (H2S) which drives up-regulation of nicotinamide phosphoribosyltransferase (Nampt). Consistent with existence of a H2S-Nampt energetic circuit, in damage recovered cancer cells, H2S, Nampt and ATP production exhibit a significant correlation. Moreover, the treatment of cancer cells with H2S donor, NaHS, coordinately increases Nampt and ATP levels, and protects cells from drug induced damage. Inhibition of cystathionine beta synthase (CBS) or cystathionase (CTH), enzymes which drive generation of H2S, decreases Nampt production while suppression of Nampt pathway by FK866, decreases H2S and ATP levels. Damage recovered cells isolated from tumors grown subcutaneously in athymic mice also show increased production of H2S, Nampt and ATP levels, associated with increased glycolysis and rapid proliferation. Together, these data show that upon recovery from potential lethal damage, H2S-Nampt directs energy expenditure and aerobic glycolysis in cancer cells, leads to their exponential growth, and causes a high degree of tolerance to damage. Identification of H2S-Nampt as a pathway responsible for induction of damage tolerance in cancer cells may underlie resistance to therapy and offers the opportunity to target this pathway as a means in treatment of cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
9. Cancer cells recovering from damage exhibit mitochondrial restructuring and increased aerobic glycolysis.
- Author
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Akakura, Shin, Ostrakhovitch, Elena, Sanokawa-Akakura, Reiko, and Tabibzadeh, Siamak
- Subjects
- *
CANCER cells , *MITOCHONDRIA , *GLYCOLYSIS , *CELL death , *MITOCHONDRIAL DNA , *CELL proliferation - Abstract
Highlights: [•] Some cancer cells recover from severe damage that causes cell death in majority of cells. [•] Damage-Recovered (DR) cancer cells show reduced mitochondria, mDNA and mitochondrial enzymes. [•] DR cells show increased aerobic glycolysis, ATP, cell proliferation, and resistance to damage. [•] DR cells recovered from in vivo damage also show increased glycolysis and proliferation rate. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
10. p53-mediated regulation of neuronal differentiation via regulation of dual oxidase maturation factor 1
- Author
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Ostrakhovitch, Elena A. and Semenikhin, Oleg A.
- Subjects
- *
P53 protein , *TRANSCRIPTION factors , *GENETIC regulation , *GENE expression , *CELL cycle , *APOPTOSIS , *CELL differentiation , *DEVELOPMENTAL neurobiology - Abstract
Abstract: The p53 transcription factor is involved in cell cycle, apoptosis and differentiation. However, the mechanism of p53 mediated differentiation is not fully understood. Here, we show that recently discovered dual oxidase maturation factor 1 (DUOXA1), which was implicated in neuronal differentiation, is regulated by p53 and may be an important factor in neuronal differentiation. We show that DUOXA1 is highly expressed in mouse neuronal stem cells with intensive nuclear localization. A strong interaction between DUOXA1 and p53 is observed in undifferentiated cells and declines in terminally differentiated neurons. Overexpressed p53 induces marked DUOXA1 expression in P19 cells and intensifies neuronal differentiation in the presence of retinoic acid, which suggests that p53 and DUOXA1 possess a neural differentiation potential. At day 3 of retinoic acid induced differentiation when cells showed a typical morphology of neuronal progenies, CD133 expression was down-regulated. The expression level of CD133 was significantly decreased in p53 over-expressing cells and was accompanied by a substantial increase in the expression level of neurofilament. In conclusion, DUOXA1 is a novel p53-regulated neurogenic factor involved in p53 dependent neuronal differentiation. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
11. Mammalian Numb-interacting Protein 1/Dual Oxidase Maturation Factor 1 Directs Neuronal Fate in Stem Cells.
- Author
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Kennedy, Karen A. M., Ostrakhovitch, Elena A., Sandiford, Shelley D. E., Dayarathna, Thamara, Xiaojun Xie, Waese, Elaine Y. L., Chang, Wing Y., Qingping Feng, Skerjanc, Iona S., Stanford, William L., and Li, Shawn S. C.
- Subjects
- *
PROTEINS , *STEM cells , *CELL differentiation , *GENE expression , *OXIDASES , *CANCER cells - Abstract
In this study, we describe a role for the mammalian Numb-interacting protein 1 (Nip1) in regulation of neuronal differentiation in stem cells. The expression of Nip1 was detected in the developing mouse brain, embryonic stem cells, primary neuronal stem cells, and retinoic acid-treated P19 embryonal carcinoma cells. The highest expression of Nip1 was observed in undifferentiated neuronal stem cells and was associated with Duox1-mediated reactive oxygen species ROS production. Ectopic nip1 expression in P19 embryonal carcinoma cells induced neuronal differentiation, and this phenotype was also linked to elevated ROS production. The neuronal differentiation in nip1-overexpressing P19 cells was achieved in a retinoic acid-independent manner and was corroborated by an increase in the expression of the neuronal basic helix-loop-helix transcription factors and neural-lineage cell markers. Furthermore, depletion of nip1 by short hairpin RNA led to a decrease in the expression of neuronal basic helix-loop-helix transcription factors and ROS. However, inhibition of ROS production in nip1-overexpressing P19 cells restricted but did not extinguish neuronal differentiation. Microarray and mass spectrometry analysis identified intermediate filaments as the principal cytoskeletal elements affected by up-regulation of nip1. We show here the first evidence for a functional interaction between Nip1 and a component of the nuclear lamina, lamin A/C. associated with a neuronal-specific phenotype. Taken together, our data reveal an important role for Nip1 in the guidance of neuronal differentiation through ROS generation and modulation of intermediate filaments and implicate Nip1 as a novel intrinsic regulator of neuronal cell fate. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
12. SAP binds to CD22 and regulates B cell inhibitory signaling and calcium flux
- Author
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Ostrakhovitch, Elena A., Wang, Yefu, and Li, Shawn S-C.
- Subjects
- *
B cell lymphoma , *PHYSIOLOGICAL effects of calcium , *LYMPHOCYTE transformation , *PROTEINS , *CELLULAR signal transduction , *LYMPHOPROLIFERATIVE disorders , *GENE expression , *IMMUNOREGULATION , *GENETICS - Abstract
Abstract: The signaling lymphocyte activation molecule (SLAM)-associated protein (SAP or SH2D1A) is an important regulator of immune function which, when mutated or deleted, causes the X-linked lymphoproliferative syndrome (XLP). Because B cell lymphoma is a major phenotype of XLP, it is important to understand the function of SAP in B cells. Here we report that SAP is expressed endogenously in mouse splenic B cells, is inducibly expressed in the human BJAB cells, and co-localizes and interacts with CD22. We also show that SAP binding to the inhibitory immunoreceptor CD22 regulates calcium mobilization in B cells. Moreover, forced expression of SAP leads to constitutive CD22 tyrosine phosphorylation and decreased Ca2+ response in B cells. Biochemical analysis reveals that, in response to IgM cross-linking, the phosphorylation of Syk, Blnk, or PLCγ2 and their interactions with one another were either diminished or completely abolished in SAP-expressing cells compared to cells that lack SAP. Collectively our work identifies a novel role for SAP in B cells and extends its function to inhibitory immunoreceptor signaling and calcium mobilization. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
13. P53 mediated regulation of metallothionein transcription in breast cancer cells.
- Author
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Ostrakhovitch, Elena A., Olsson, Per-Erik, von Hofsten, Jonas, and Cherian, M. George
- Published
- 2007
- Full Text
- View/download PDF
14. Stimulation of phosphoinositide 3-kinase/Akt signaling by copper and zinc ions: Mechanisms and consequences
- Author
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Barthel, Andreas, Ostrakhovitch, Elena A., Walter, Philippe L., Kampkötter, Andreas, and Klotz, Lars-Oliver
- Subjects
- *
PHOSPHOINOSITIDES , *CELLULAR control mechanisms , *COPPER ions , *ZINC - Abstract
Abstract: The phosphoinositide 3′-kinase (PI3K)/Akt signaling cascade controls cellular processes such as apoptosis and proliferation. Moreover, it is a mediator of insulin effects on target cells and as such is a major regulator of fuel metabolism. The PI3K/Akt cascade was demonstrated to be activated by stressful stimuli, including heat shock and reactive oxygen species (ROS). This minireview focuses on activation of the pathway by exposure of cells to heavy metal ions, Cu2+ and Zn2+. It is hypothesized that stimulation of PI3K/Akt is the molecular mechanism underlying the known insulin-mimetic effects of copper and zinc ions. Following a brief summary of PI3K/Akt signaling and of activation of the cascade by Cu2+ and Zn2+, mechanisms of metal-induced PI3K/Akt activation are discussed with a focus on the role of ROS and of cellular thiols (glutathione, thioredoxin) and protein tyrosine phosphatases in Cu2+ and Zn2+ signaling. Finally, consequences of metal-induced PI3K/Akt activation are discussed, focusing on the modulation of FoxO-family transcription factors by Cu2+ and Zn2+. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
15. Copper Ions Strongly Activate the Phosphoinositide-3-Kinase/Akt Pathway Independent of the Generation of Reactive Oxygen Species
- Author
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Ostrakhovitch, Elena A., Lordnejad, Mohammad Reza, Schliess, Freimut, Sies, Helmut, and Klotz, Lars-Oliver
- Subjects
- *
HEAVY metals , *PROTEIN kinases , *GENETIC transduction - Abstract
Copper is implicated in metabolic disorders, such as Wilson''s disease or Alzheimer''s disease. Analysis of signaling pathways regulating cellular survival and function in response to a copper stress is crucial for understanding the pathogenesis of such diseases. Exposure of human skin fibroblasts or HeLa cells to Cu2+ resulted in a dose- and time-dependent activation of the antiapoptotic kinase Akt/protein kinase B, starting at concentrations as low as 3 μM. Only Cu(II), but not Cu(I), had this effect. Activation of Akt was accompanied by phosphorylation of a downstream target of Akt, glycogen synthase kinase-3. Inhibitors of phosphoinositide-3-kinase (PI3K) completely blocked activation of Akt by Cu2+, indicating a requirement of PI3K for Cu2+-induced activation of Akt. Indeed, cellular PI3K activity was strongly enhanced after exposure to Cu2+. Copper ions may lead to the formation of reactive oxygen species, such as hydrogen peroxide. Activation of Akt by hydrogen peroxide or growth factors is known to proceed via the activation growth factor receptors. In line with this, pretreatment with inhibitors of growth factor receptor tyrosine kinases blocked activation of Akt by hydrogen peroxide and growth factors, as did a src-family tyrosine kinase inhibitor or the broad-spectrum tyrosine kinase inhibitor genistein. Activation of Akt by Cu2+, however, remained unimpaired, implying (i) that tyrosine kinase activation is not involved in Cu2+ activation of Akt and (ii) that activation of the PI3K/Akt pathway by Cu2+ is initiated independently of that induced by reactive oxygen species. Comparison of the time course of the oxidation of 2′,7′-dichlorodihydrofluorescein in copper-treated cells with that of Akt activation led to the conclusion that production of hydroperoxides cannot be an upstream event in copper-induced Akt activation. Rather, both activation of Akt and generation of ROS are proposed to occur in parallel, regulating cell survival after a copper stress. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
16. 3-Mercaptopyruvate sulfurtransferase disruption in dermal fibroblasts facilitates adipogenic trans-differentiation.
- Author
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Ostrakhovitch, Elena A., Akakura, Shin, Sanokawa-Akakura, Reiko, and Tabibzadeh, Siamak
- Subjects
- *
ADIPOGENESIS , *MESENCHYMAL stem cell differentiation , *FIBROBLASTS , *SOX2 protein , *GENE silencing - Abstract
Transitioning from a differentiated state to a higher-order of plasticity, by partial rather than full reactivation of pluripotency genes, might be a better approach in regenerative medicine. Hydrogen sulfide plays a crucial role in the maintenance and differentiation of mesenchymal stem cells (MSC) that have the potential to differentiate to a diverse group of mesenchymally derived cells. It was shown that these cells show a heavy reliance on cystathionine-β-synthase (CBS)-derived hydrogen sulfide (H 2 S) during differentiation. We have found that expression and activity of 3-mercaptopyruvate sulfurtransferase (MPST), one of three enzymes that hat regulates H 2 S biosynthesis, is significantly lower in MSC as compared with lineage-restricted dermal fibroblasts. Here, we tested the hypothesis that suppression of MPST in dermal fibroblasts might induce plasticity-related changes and broaden the transdifferentiation potency. Inactivation of MPST with phenylpyruvate (PP) or by siRNA silencing led to diminished H 2 S production associated with increased production of reactive oxygen species (ROS) and lactic acid. Accumulation of α-ketoglutarate (α-KG), a key metabolite required for the expression of ten-eleven translocation hydroxylase (TET), was associated with stimulated transcription of pluripotency related genes including OCT4 , KLF4 , SOX2 , and NANOG. Suppression of TET1 gene and inhibition of glycolysis with glucose analog, 2-desoxy- d -glucose, or hexokinase II inhibitor significantly reduced expression of pluripotency genes following MPST inactivation or knockdown. MPST disruption promoted the conversion of fibroblasts into adipocytes as evidenced by a significant increase in expression of adipocyte-specific genes, PPARγ, and UCP1 , and intracellular accumulation of oil Red-O positive fat droplets. Inhibition of glycolysis inhibited these changes. Under induced differentiation conditions, fibroblasts with disrupted MPST show the potency to differentiate to white adipogenic lineage. Thus, MPST inactivation or silencing enhances the plasticity of dermal fibroblasts in a TET1 and glycolysis dependent manner and promotes adipogenic transdifferentiation. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
17. Direct enzymatic reduction of lucigenin decreases lucigenin-amplified chemiluminescence produced by superoxide ion.
- Author
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Afanas'ev, Igor B., Ostrakhovitch, Elena A., Mikhal'chik, Elena V., and Korkina, Ludmila G.
- Published
- 2001
- Full Text
- View/download PDF
18. In the wake of neural progenitors
- Author
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Ostrakhovitch, Elena
- Published
- 2013
- Full Text
- View/download PDF
19. Highlight section: Copper and zinc in cell signaling and disease
- Author
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Ostrakhovitch, Elena A. and Klotz, Lars-Oliver
- Published
- 2007
- Full Text
- View/download PDF
20. Replicative senescence is distinguishable from DNA damage-induced senescence by increased methylation of promoter of rDNA and reduced expression of rRNA.
- Author
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Sanokawa-Akakura R, Akakura S, Ostrakhovitch EA, and Tabibzadeh S
- Subjects
- Humans, Cellular Senescence, DNA Damage, DNA Methylation, DNA, Ribosomal biosynthesis, Fibroblasts metabolism, Gene Expression Regulation, RNA, Ribosomal biosynthesis
- Abstract
Human fibroblasts become senescent after a limited number of replications or by diverse stresses, such as DNA damage. However, replicative and damage induced senescence are indistinguishable in respect to proliferation cessation and expression of senescence markers, senescence-associated β-galactosidase, p16 and p21. Here, we show that senescence types can be distinguished by reduced levels of 18S, 5.8S and 28S rRNA, in replicative but not induced senescence. We also demonstrate that promoter region of rRNA is hypermethylated in replicative senescence. The findings show that expression level of rRNA or methylation of its promoter can be used to distinguish between senescence types., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
21. Homocysteine in Chronic Kidney Disease.
- Author
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Ostrakhovitch EA and Tabibzadeh S
- Subjects
- Humans, Methylation, Oxidation-Reduction, Oxidative Stress, Homocysteine blood, Hyperhomocysteinemia etiology, Kidney Failure, Chronic blood
- Abstract
Hyperhomocysteinemia occurs in chronic- and end-stage kidney disease at the time when dialysis or transplant becomes indispensable for survival. Excessive accumulation of homocysteine (Hcy) aggravates conditions associated with imbalanced homeostasis and cellular redox thereby resulting in severe oxidative stress leading to oxidation of reduced free and protein-bound thiols. Thiol modifications such as N-homocysteinylation, sulfination, cysteinylation, glutathionylation, and sulfhydration control cellular responses that direct complex metabolic pathways. Although cysteinyl modifications are kept low, under Hcy-induced stress, thiol modifications persist thus surpassing cellular proteostasis. Here, we review mechanisms of redox regulation and show how cysteinyl modifications triggered by excess Hcy contribute development and progression of chronic kidney disease. We discuss different signaling events resulting from aberrant cysteinyl modification with a focus on transsulfuration., (© 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
22. Inhibition of extracellular signal regulated kinase (ERK) leads to apoptosis inducing factor (AIF) mediated apoptosis in epithelial breast cancer cells: the lack of effect of ERK in p53 mediated copper induced apoptosis.
- Author
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Ostrakhovitch EA and Cherian MG
- Subjects
- Breast Neoplasms pathology, Cell Line, Tumor, Enzyme Activation drug effects, Epithelial Cells metabolism, Epithelial Cells pathology, Extracellular Signal-Regulated MAP Kinases metabolism, Flavonoids pharmacology, Humans, Protein Kinase Inhibitors pharmacology, Reactive Oxygen Species metabolism, Zinc pharmacology, Apoptosis drug effects, Breast Neoplasms metabolism, Copper pharmacology, Epithelial Cells drug effects, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Tumor Suppressor Protein p53 metabolism
- Abstract
Recent studies have shown that MEK/ERK-mediated signals play a major role in regulation of activity of p53 tumor suppressor protein. In this study, we investigated whether or not there is functional interaction between p53 and MEK/ERK pathways in epithelial breast cancer cells exposed to copper or zinc. We demonstrated that expression of wild-type p53 induced by copper or zinc significantly reduced phosphorylation of extracellular signal regulated kinase (ERK) in epithelial breast cancer MCF7 cells. Mutation or suppression of p53 in MDA-MB231 and MCF7-E6 cells, respectively, resulted in a strong ERK phosphorylation in the presence of metals. Weak ERK phosphorylation in MCF7 cells induced by copper or zinc was linked to mitochondrial disruption and apoptosis. Furthermore, inhibition of ERK through addition of PD98059 stimulated p53 activation in MCF7 cells and also led to upregulation of p53 downstream targets, p21 and Bax, which is a proapototic member of Bcl-2 family triggering mitochondrial pore opening. Moreover, blockage of the MEK/ERK pathway caused a breakdown of the mitochondrial membrane potential accompanied by an elevation in the ROS production. Disruption of p53 expression attenuated the depolarization of the mitochondrial membrane and ROS generation. Furthermore, PD98059 initiated apoptosis inducing factor (AIF) translocation from mitochondria to the nucleus in MCF7 cells; which are depleted in caspase 3. Interestingly, repression of MEK/ERK pathway did not intensify the cell stress caused by metal toxicity. Therefore, these findings demonstrate that MEK/ERK pathway plays an important role in downregulation of p53 and cell survival. Inhibition of ERK can lead to apoptosis via nuclear relocation of AIF. However, metal-induced activation of p53 and mitochondrial depolarization appears to be independent of ERK. Our data suggest that copper induces apoptosis through depolarization of mitochondrial membrane with release of AIF, and this process is MEK/ERK independent.
- Published
- 2005
- Full Text
- View/download PDF
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