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Article ; Online: Mechanisms of ferroptosis.

Cao, Jennifer Yinuo / Dixon, Scott J

Cellular and molecular life sciences : CMLS

2016 Volume 73, Issue 11-12, Page(s) 2195–2209

Abstract: Ferroptosis is a non-apoptotic form of cell death that can be triggered by small molecules or conditions that inhibit glutathione biosynthesis or the glutathione-dependent antioxidant enzyme glutathione peroxidase 4 (GPX4). This lethal process is defined ...

Abstract	Ferroptosis is a non-apoptotic form of cell death that can be triggered by small molecules or conditions that inhibit glutathione biosynthesis or the glutathione-dependent antioxidant enzyme glutathione peroxidase 4 (GPX4). This lethal process is defined by the iron-dependent accumulation of lipid reactive oxygen species and depletion of plasma membrane polyunsaturated fatty acids. Cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression may be sensitized to this process. Conversely, a number of small molecule inhibitors of ferroptosis have been identified, including ferrostatin-1 and liproxstatin-1, which can block pathological cell death events in brain, kidney and other tissues. Recent work has identified a number of genes required for ferroptosis, including those involved in lipid and amino acid metabolism. Outstanding questions include the relationship between ferroptosis and other forms of cell death, and whether activation or inhibition of ferroptosis can be exploited to achieve desirable therapeutic ends.
MeSH term(s)	Cell Death/physiology ; Cell Membrane/pathology ; Cyclohexylamines/pharmacology ; Fatty Acids, Unsaturated/metabolism ; Glutathione/biosynthesis ; Glutathione/metabolism ; Glutathione Peroxidase/biosynthesis ; Glutathione Peroxidase/metabolism ; Iron/metabolism ; Neoplasms/pathology ; Phenylenediamines/pharmacology ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Quinoxalines/pharmacology ; Reactive Oxygen Species/metabolism ; Spiro Compounds/pharmacology
Chemical Substances	Cyclohexylamines ; Fatty Acids, Unsaturated ; Phenylenediamines ; Quinoxalines ; Reactive Oxygen Species ; Spiro Compounds ; ferrostatin-1 ; liproxstatin-1 ; Iron (E1UOL152H7) ; Phospholipid Hydroperoxide Glutathione Peroxidase (EC 1.11.1.12) ; Glutathione Peroxidase (EC 1.11.1.9) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2016-04-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-016-2194-1
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Article: Mechanisms of ferroptosis

Cao, Jennifer Yinuo / Scott J. Dixon

Cellular and molecular life sciences. 2016 June, v. 73, no. 11-12

2016

Abstract	Ferroptosis is a non-apoptotic form of cell death that can be triggered by small molecules or conditions that inhibit glutathione biosynthesis or the glutathione-dependent antioxidant enzyme glutathione peroxidase 4 (GPX4). This lethal process is defined by the iron-dependent accumulation of lipid reactive oxygen species and depletion of plasma membrane polyunsaturated fatty acids. Cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression may be sensitized to this process. Conversely, a number of small molecule inhibitors of ferroptosis have been identified, including ferrostatin-1 and liproxstatin-1, which can block pathological cell death events in brain, kidney and other tissues. Recent work has identified a number of genes required for ferroptosis, including those involved in lipid and amino acid metabolism. Outstanding questions include the relationship between ferroptosis and other forms of cell death, and whether activation or inhibition of ferroptosis can be exploited to achieve desirable therapeutic ends.
Keywords	amino acid metabolism ; antioxidants ; biosynthesis ; brain ; cell death ; genes ; glutathione ; kidneys ; neoplasm cells ; phospholipid-hydroperoxide glutathione peroxidase ; plasma membrane ; polyunsaturated fatty acids ; reactive oxygen species ; tissues
Language	English
Dates of publication	2016-06
Size	p. 2195-2209.
Publishing place	Springer International Publishing
Document type	Article
Note	Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-016-2194-1
Database	NAL-Catalogue (AGRICOLA)

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Article: Systematic Quantification of Population Cell Death Kinetics in Mammalian Cells.

Forcina, Giovanni C / Conlon, Megan / Wells, Alex / Cao, Jennifer Yinuo / Dixon, Scott J

Cell systems

2017 Volume 4, Issue 6, Page(s) 600–610.e6

Abstract: Cytotoxic compounds are important drugs and research tools. Here, we introduce a method, scalable time-lapse analysis of cell death kinetics (STACK), to quantify the kinetics of compound-induced cell death in mammalian cells at the population level. ... ...

Abstract	Cytotoxic compounds are important drugs and research tools. Here, we introduce a method, scalable time-lapse analysis of cell death kinetics (STACK), to quantify the kinetics of compound-induced cell death in mammalian cells at the population level. STACK uses live and dead cell markers, high-throughput time-lapse imaging, and mathematical modeling to determine the kinetics of population cell death over time. We used STACK to profile the effects of over 1,800 bioactive compounds on cell death in two human cancer cell lines, resulting in a large and freely available dataset. 79 potent lethal compounds common to both cell lines caused cell death with widely divergent kinetics. 13 compounds triggered cell death within hours, including the metallophore zinc pyrithione. Mechanistic studies demonstrated that this rapid onset lethal phenotype was caused in human cancer cells by metabolic disruption and ATP depletion. These results provide the first comprehensive survey of cell death kinetics and analysis of rapid-onset lethal compounds.
MeSH term(s)	A549 Cells ; Animals ; Biomarkers/metabolism ; Cell Death/physiology ; Cell Line, Tumor ; Humans ; Kinetics ; Mammals/metabolism ; Mammals/physiology
Chemical Substances	Biomarkers
Language	English
Publishing date	2017-06-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2405-4712
ISSN	2405-4712
DOI	10.1016/j.cels.2017.05.002
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Article ; Online: A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity.

Cao, Jennifer Yinuo / Poddar, Aunoy / Magtanong, Leslie / Lumb, Jennifer H / Mileur, Trevor R / Reid, Michael A / Dovey, Cole M / Wang, Jin / Locasale, Jason W / Stone, Everett / Cole, Susan P C / Carette, Jan E / Dixon, Scott J

Cell reports

2019 Volume 26, Issue 6, Page(s) 1544–1556.e8

Abstract: The tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters ferroptosis sensitivity is poorly understood. Using genome-wide ... ...

Abstract	The tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters ferroptosis sensitivity is poorly understood. Using genome-wide human haploid genetic screening technology coupled to fluorescence-activated cell sorting (FACS), we directly identify genes that regulate intracellular glutathione abundance and characterize their role in ferroptosis regulation. Disruption of the ATP binding cassette (ABC)-family transporter multidrug resistance protein 1 (MRP1) prevents glutathione efflux from the cell and strongly inhibits ferroptosis. High levels of MRP1 expression decrease sensitivity to certain pro-apoptotic chemotherapeutic drugs, while collaterally sensitizing to all tested pro-ferroptotic agents. By contrast, disruption of KEAP1 and NAA38, leading to the stabilization of the transcription factor NRF2, increases glutathione levels but only weakly protects from ferroptosis. This is due in part to concomitant NRF2-mediated upregulation of MRP1. These results pinpoint glutathione efflux as an unanticipated regulator of ferroptosis sensitivity.
MeSH term(s)	Cell Line, Tumor ; Female ; Ferroptosis/genetics ; Flow Cytometry/methods ; Genome, Human ; Glutathione/metabolism ; Haploidy ; Humans ; Kelch-Like ECH-Associated Protein 1/genetics ; Kelch-Like ECH-Associated Protein 1/metabolism ; Male ; Multidrug Resistance-Associated Proteins/genetics ; Multidrug Resistance-Associated Proteins/metabolism ; N-Terminal Acetyltransferase C/genetics ; N-Terminal Acetyltransferase C/metabolism ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Ribonucleoprotein, U4-U6 Small Nuclear/genetics ; Ribonucleoprotein, U4-U6 Small Nuclear/metabolism
Chemical Substances	KEAP1 protein, human ; Kelch-Like ECH-Associated Protein 1 ; Multidrug Resistance-Associated Proteins ; NAA38 protein, human ; NF-E2-Related Factor 2 ; NFE2L2 protein, human ; Ribonucleoprotein, U4-U6 Small Nuclear ; N-Terminal Acetyltransferase C (EC 2.3.1.256) ; Glutathione (GAN16C9B8O) ; multidrug resistance-associated protein 1 (Y49M64GZ4Q)
Language	English
Publishing date	2019-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.01.043
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Article ; Online: A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity

Jennifer Yinuo Cao / Aunoy Poddar / Leslie Magtanong / Jennifer H. Lumb / Trevor R. Mileur / Michael A. Reid / Cole M. Dovey / Jin Wang / Jason W. Locasale / Everett Stone / Susan P.C. Cole / Jan E. Carette / Scott J. Dixon

Cell Reports, Vol 26, Iss 6, Pp 1544-1556.e

2019 Volume 8

Abstract: ... human haploid cell mutagenesis and FACS-based detection, Cao et al. identify negative regulators ...

Abstract	Summary: The tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters ferroptosis sensitivity is poorly understood. Using genome-wide human haploid genetic screening technology coupled to fluorescence-activated cell sorting (FACS), we directly identify genes that regulate intracellular glutathione abundance and characterize their role in ferroptosis regulation. Disruption of the ATP binding cassette (ABC)-family transporter multidrug resistance protein 1 (MRP1) prevents glutathione efflux from the cell and strongly inhibits ferroptosis. High levels of MRP1 expression decrease sensitivity to certain pro-apoptotic chemotherapeutic drugs, while collaterally sensitizing to all tested pro-ferroptotic agents. By contrast, disruption of KEAP1 and NAA38, leading to the stabilization of the transcription factor NRF2, increases glutathione levels but only weakly protects from ferroptosis. This is due in part to concomitant NRF2-mediated upregulation of MRP1. These results pinpoint glutathione efflux as an unanticipated regulator of ferroptosis sensitivity. : Glutathione suppresses the non-apoptotic cell death process of ferroptosis. Using genome-wide human haploid cell mutagenesis and FACS-based detection, Cao et al. identify negative regulators of intracellular glutathione abundance that affect glutathione efflux and NRF2 protein levels, altering ferroptosis sensitivity. Keywords: ROS, metabolite efflux, multidrug resistance, ferroptosis, necrosis, cancer, glutathione, iron, collateral sensitivity
Keywords	Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2019-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Changes in the nasopharyngeal carcinoma nuclear proteome induced by the EBNA1 protein of Epstein-Barr virus reveal potential roles for EBNA1 in metastasis and oxidative stress responses.

Cao, Jennifer Yinuo / Mansouri, Sheila / Frappier, Lori

Journal of virology

2011 Volume 86, Issue 1, Page(s) 382–394

Abstract: Epstein-Barr virus (EBV) infection is causatively associated with a variety of human cancers, including nasopharyngeal carcinoma (NPC). The only viral nuclear protein expressed in NPC is EBNA1, which can alter cellular properties in ways that may promote ...

Abstract	Epstein-Barr virus (EBV) infection is causatively associated with a variety of human cancers, including nasopharyngeal carcinoma (NPC). The only viral nuclear protein expressed in NPC is EBNA1, which can alter cellular properties in ways that may promote oncogenesis. Here, we used 2-dimensional difference gel electrophoresis (2-D DiGE) to profile changes in the nuclear proteome that occur after stable expression of EBNA1 in the EBV-negative NPC cell line CNE2. We found that EBNA1 consistently altered the levels of a small percentage of the nuclear proteins. The identification of 19 of these proteins by mass spectrometry revealed that EBNA1 upregulated three proteins affecting metastatic potential (stathmin 1, maspin, and Nm23-H1) and several proteins in the oxidative stress response pathway, including the antioxidants superoxide dismutase 1 (SOD1) and peroxiredoxin 1 (Prx1). Western blot analysis verified that EBNA1 expression upregulated and EBNA1 silencing downregulated these proteins. In addition, transcripts for stathmin 1 were induced by EBNA1, whereas EBNA1 only affected Prx1 and SOD1 at the protein level. Further investigation of the EBNA1 effects on the redox pathway showed that long-term EBNA1 expression in NPC resulted in increased reactive oxygen species (ROS) and increased levels of the NADPH oxidases NOX1 and NOX2, known to generate ROS. In addition, EBNA1 depletion in EBV-positive cells decreased NOX2 and ROS. The results show multiple roles for EBNA1 in the oxidative stress response pathway and suggest mechanisms by which EBNA1 may promote NPC metastases.
MeSH term(s)	Carcinoma ; Cell Line, Tumor ; Cell Nucleus/chemistry ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Epstein-Barr Virus Infections/genetics ; Epstein-Barr Virus Infections/metabolism ; Epstein-Barr Virus Infections/pathology ; Epstein-Barr Virus Infections/virology ; Epstein-Barr Virus Nuclear Antigens/genetics ; Epstein-Barr Virus Nuclear Antigens/metabolism ; Gene Expression Regulation ; Herpesvirus 4, Human/genetics ; Herpesvirus 4, Human/metabolism ; Humans ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms/genetics ; Nasopharyngeal Neoplasms/metabolism ; Nasopharyngeal Neoplasms/pathology ; Nasopharyngeal Neoplasms/virology ; Neoplasm Metastasis ; Oxidative Stress ; Proteome/chemistry ; Proteome/genetics ; Proteome/metabolism ; Two-Dimensional Difference Gel Electrophoresis
Chemical Substances	Epstein-Barr Virus Nuclear Antigens ; Proteome ; EBV-encoded nuclear antigen 1 (O5GA75RST7)
Language	English
Publishing date	2011-10-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.05648-11
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Article ; Online: Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State.

Magtanong, Leslie / Ko, Pin-Joe / To, Milton / Cao, Jennifer Yinuo / Forcina, Giovanni C / Tarangelo, Amy / Ward, Carl C / Cho, Kevin / Patti, Gary J / Nomura, Daniel K / Olzmann, James A / Dixon, Scott J

Cell chemical biology

2019 Volume 26, Issue 3, Page(s) 420–432.e9

Abstract: The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently ... ...

Abstract	The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state.
MeSH term(s)	Animals ; Arachidonic Acid/chemistry ; Arachidonic Acid/metabolism ; Arachidonic Acid/pharmacology ; Cell Line ; Cell Membrane/chemistry ; Cell Membrane/metabolism ; Coenzyme A Ligases/metabolism ; Fatty Acids, Monounsaturated/chemistry ; Fatty Acids, Monounsaturated/metabolism ; Fatty Acids, Monounsaturated/pharmacology ; Ferroptosis/drug effects ; Lipid Droplets/chemistry ; Lipid Droplets/metabolism ; Lipids/chemistry ; Mice ; Oxidation-Reduction ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Reactive Oxygen Species/chemistry ; Reactive Oxygen Species/metabolism
Chemical Substances	Fatty Acids, Monounsaturated ; Lipids ; Reactive Oxygen Species ; Arachidonic Acid (27YG812J1I) ; Phospholipid Hydroperoxide Glutathione Peroxidase (EC 1.11.1.12) ; glutathione peroxidase 4, mouse (EC 1.11.1.9) ; Acsl3 protein, mouse (EC 6.1.2.3) ; Coenzyme A Ligases (EC 6.2.1.-)
Language	English
Publishing date	2019-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2018.11.016
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Identification of a Novel Protein Interaction Motif in the Regulatory Subunit of Casein Kinase 2

Cao, Jennifer Yinuo / Shire, Kathy / Landry, Cameron / Gish, Gerald D. / Pawson, Tony / Frappier, Lori

Molecular and Cellular Biology. 2014 Jan. 1, v. 34, no. 2 p.246-258

2014

Abstract: Casein kinase 2 (CK2) regulates multiple cellular processes and can promote oncogenesis. Interactions with the CK2β regulatory subunit of the enzyme target its catalytic subunit (CK2α or CK2α′) to specific substrates; however, little is known about the ... ...

Abstract	Casein kinase 2 (CK2) regulates multiple cellular processes and can promote oncogenesis. Interactions with the CK2β regulatory subunit of the enzyme target its catalytic subunit (CK2α or CK2α′) to specific substrates; however, little is known about the mechanisms by which these interactions occur. We previously showed that by binding CK2β, the Epstein-Barr virus (EBV) EBNA1 protein recruits CK2 to promyelocytic leukemia (PML) nuclear bodies, where increased CK2-mediated phosphorylation of PML proteins triggers their degradation. Here we have identified a KSSR motif near the dimerization interface of CK2β as forming part of a protein interaction pocket that mediates interaction with EBNA1. We show that the EBNA1-CK2β interaction is primed by phosphorylation of EBNA1 on S393 (within a polyserine region). This phosphoserine is critical for EBNA1-induced PML degradation but does not affect EBNA1 functions in EBV replication or segregation. Using comparative proteomics of wild-type (WT) and KSSR mutant CK2β, we identified an uncharacterized cellular protein, C18orf25/ARKL1, that also binds CK2β through the KSSR motif and show that this involves a polyserine sequence resembling the CK2β binding sequence in EBNA1. Therefore, we have identified a new mechanism of CK2 interaction used by viral and cellular proteins.
Keywords	Human gammaherpesvirus 4 ; carcinogenesis ; cell biology ; dimerization ; leukemia ; mutants ; non-specific serine/threonine protein kinase ; phosphorylation ; protein subunits ; proteomics
Language	English
Dates of publication	2014-0101
Size	p. 246-258.
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00968-13
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Article ; Online: Epstein-Barr virus nuclear antigen 1 Hijacks the host kinase CK2 to disrupt PML nuclear bodies.

Sivachandran, Nirojini / Cao, Jennifer Yinuo / Frappier, Lori

Journal of virology

2010 Volume 84, Issue 21, Page(s) 11113–11123

Abstract: Latent Epstein-Barr virus (EBV) infection is an important causative factor in the development of several cancers, including nasopharyngeal carcinoma (NPC). The one EBV protein expressed in the nucleus of NPC cells, EBNA1, has been shown to disrupt ... ...

Abstract	Latent Epstein-Barr virus (EBV) infection is an important causative factor in the development of several cancers, including nasopharyngeal carcinoma (NPC). The one EBV protein expressed in the nucleus of NPC cells, EBNA1, has been shown to disrupt promyelocitic leukemia (PML) nuclear bodies (NBs) by inducing the degradation of PML proteins, leading to impaired DNA repair and increased cell survival. Although EBNA1-mediated PML disruption is likely to be an important factor in the development of NPC, little is known about its mechanism. We now show that an interaction between EBNA1 and the host CK2 kinase is crucial for EBNA1 to disrupt PML bodies and degrade PML proteins. EBNA1 increases the association of CK2 with PML proteins, thereby increasing the phosphorylation of PML proteins by CK2, a modification that is known to trigger the polyubiquitylation and degradation of PML. The interaction between EBNA1 and CK2 is direct and occurs through the β regulatory subunit of CK2 and EBNA1 amino acids 387 to 394. The binding of EBNA1 to the host ubiquitin specific protease USP7 has also been shown to be important for EBNA1-mediated PML disruption. We show that EBNA1 also increases the occupancy of USP7 at PML NBs and that CK2 and USP7 bind independently and simultaneously to EBNA1 to form a ternary complex. The combined results indicate that EBNA1 usurps two independent cellular pathways to trigger the loss of PML NBs.
MeSH term(s)	Binding Sites ; Casein Kinase II/metabolism ; Cell Line, Tumor ; Epstein-Barr Virus Nuclear Antigens/physiology ; Herpesvirus 4, Human/pathogenicity ; Host-Pathogen Interactions ; Humans ; Intranuclear Inclusion Bodies/metabolism ; Nasopharyngeal Neoplasms/etiology ; Nuclear Proteins/metabolism ; Phosphorylation ; Promyelocytic Leukemia Protein ; Protein Binding ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism ; Ubiquitin Thiolesterase/metabolism ; Ubiquitin-Specific Peptidase 7
Chemical Substances	Epstein-Barr Virus Nuclear Antigens ; Nuclear Proteins ; Promyelocytic Leukemia Protein ; Transcription Factors ; Tumor Suppressor Proteins ; PML protein, human (143220-95-5) ; Casein Kinase II (EC 2.7.11.1) ; USP7 protein, human (EC 3.4.19.12) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Ubiquitin-Specific Peptidase 7 (EC 3.4.19.12) ; EBV-encoded nuclear antigen 1 (O5GA75RST7)
Language	English
Publishing date	2010-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01183-10
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Article ; Online: Identification of a novel protein interaction motif in the regulatory subunit of casein kinase 2.

Cao, Jennifer Yinuo / Shire, Kathy / Landry, Cameron / Gish, Gerald D / Pawson, Tony / Frappier, Lori

Molecular and cellular biology

2013 Volume 34, Issue 2, Page(s) 246–258

Abstract: Casein kinase 2 (CK2) regulates multiple cellular processes and can promote oncogenesis. Interactions with the CK2β regulatory subunit of the enzyme target its catalytic subunit (CK2α or CK2α') to specific substrates; however, little is known about the ... ...

Abstract	Casein kinase 2 (CK2) regulates multiple cellular processes and can promote oncogenesis. Interactions with the CK2β regulatory subunit of the enzyme target its catalytic subunit (CK2α or CK2α') to specific substrates; however, little is known about the mechanisms by which these interactions occur. We previously showed that by binding CK2β, the Epstein-Barr virus (EBV) EBNA1 protein recruits CK2 to promyelocytic leukemia (PML) nuclear bodies, where increased CK2-mediated phosphorylation of PML proteins triggers their degradation. Here we have identified a KSSR motif near the dimerization interface of CK2β as forming part of a protein interaction pocket that mediates interaction with EBNA1. We show that the EBNA1-CK2β interaction is primed by phosphorylation of EBNA1 on S393 (within a polyserine region). This phosphoserine is critical for EBNA1-induced PML degradation but does not affect EBNA1 functions in EBV replication or segregation. Using comparative proteomics of wild-type (WT) and KSSR mutant CK2β, we identified an uncharacterized cellular protein, C18orf25/ARKL1, that also binds CK2β through the KSSR motif and show that this involves a polyserine sequence resembling the CK2β binding sequence in EBNA1. Therefore, we have identified a new mechanism of CK2 interaction used by viral and cellular proteins.
MeSH term(s)	Active Transport, Cell Nucleus ; Adaptor Proteins, Signal Transducing ; Amino Acid Sequence ; Amino Acid Substitution ; Binding Sites ; Carrier Proteins/metabolism ; Casein Kinase II/chemistry ; Casein Kinase II/metabolism ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Epstein-Barr Virus Nuclear Antigens/genetics ; Epstein-Barr Virus Nuclear Antigens/metabolism ; HEK293 Cells ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Phosphorylation ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Interaction Mapping ; Protein Processing, Post-Translational ; Protein Structure, Secondary
Chemical Substances	Adaptor Proteins, Signal Transducing ; C18ORF25 protein, human ; Carrier Proteins ; Epstein-Barr Virus Nuclear Antigens ; Casein Kinase II (EC 2.7.11.1) ; EBV-encoded nuclear antigen 1 (O5GA75RST7)
Language	English
Publishing date	2013-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00968-13
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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