The nucleocapsid protein of severe acute respiratory syndrome-coronavirus inhibits the activity of cyclin-cyclin-dependent kinase complex and blocks S phase progression in mammalian cells.
Identifieur interne : 003C57 ( Main/Exploration ); précédent : 003C56; suivant : 003C58The nucleocapsid protein of severe acute respiratory syndrome-coronavirus inhibits the activity of cyclin-cyclin-dependent kinase complex and blocks S phase progression in mammalian cells.
Auteurs : Milan Surjit [Inde] ; Boping Liu ; Vincent T K. Chow ; Sunil K. LalSource :
- The Journal of biological chemistry [ 0021-9258 ] ; 2006.
Descripteurs français
- KwdFr :
- Activation de la transcription, Animaux, Biosynthèse des protéines, Broxuridine (pharmacologie), Cellules COS, Chloramphenicol O-acetyltransferase (métabolisme), Cycle cellulaire, Cycline A (métabolisme), Cycline E (métabolisme), Cytométrie en flux, Données de séquences moléculaires, Facteur de transcription E2F1 (métabolisme), Facteurs temps, Immunoprécipitation, Immunotransfert, Kinase-2 cycline-dépendante (métabolisme), Kinases cyclines-dépendantes (métabolisme), Liaison aux protéines, Lignée cellulaire, Mutation, Phase S, Phosphorylation, Plasmides (métabolisme), Protéine du rétinoblastome (métabolisme), Protéines nucléocapside (physiologie), Relation dose-effet des médicaments, Régulation négative, Structure tertiaire des protéines, Séparation cellulaire, Séquence nucléotidique, Transcription génétique, Électrophorèse sur gel de polyacrylamide.
- MESH :
- métabolisme : Chloramphenicol O-acetyltransferase, Cycline A, Cycline E, Facteur de transcription E2F1, Kinase-2 cycline-dépendante, Kinases cyclines-dépendantes, Plasmides, Protéine du rétinoblastome.
- pharmacologie : Broxuridine.
- physiologie : Protéines nucléocapside.
- Activation de la transcription, Animaux, Biosynthèse des protéines, Cellules COS, Cycle cellulaire, Cytométrie en flux, Données de séquences moléculaires, Facteurs temps, Immunoprécipitation, Immunotransfert, Liaison aux protéines, Lignée cellulaire, Mutation, Phase S, Phosphorylation, Relation dose-effet des médicaments, Régulation négative, Structure tertiaire des protéines, Séparation cellulaire, Séquence nucléotidique, Transcription génétique, Électrophorèse sur gel de polyacrylamide.
English descriptors
- KwdEn :
- Animals, Base Sequence, Bromodeoxyuridine (pharmacology), COS Cells, Cell Cycle, Cell Line, Cell Separation, Chloramphenicol O-Acetyltransferase (metabolism), Chlorocebus aethiops, Cyclin A (metabolism), Cyclin E (metabolism), Cyclin-Dependent Kinase 2 (metabolism), Cyclin-Dependent Kinases (metabolism), Dose-Response Relationship, Drug, Down-Regulation, E2F1 Transcription Factor (metabolism), Electrophoresis, Polyacrylamide Gel, Flow Cytometry, Immunoblotting, Immunoprecipitation, Molecular Sequence Data, Mutation, Nucleocapsid Proteins (physiology), Phosphorylation, Plasmids (metabolism), Protein Binding, Protein Biosynthesis, Protein Structure, Tertiary, Retinoblastoma Protein (metabolism), S Phase, Time Factors, Transcription, Genetic, Transcriptional Activation.
- MESH :
- chemical , metabolism : Chloramphenicol O-Acetyltransferase, Cyclin A, Cyclin E, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, E2F1 Transcription Factor, Retinoblastoma Protein.
- chemical , pharmacology : Bromodeoxyuridine.
- chemical , physiology : Nucleocapsid Proteins.
- metabolism : Plasmids.
- Animals, Base Sequence, COS Cells, Cell Cycle, Cell Line, Cell Separation, Chlorocebus aethiops, Dose-Response Relationship, Drug, Down-Regulation, Electrophoresis, Polyacrylamide Gel, Flow Cytometry, Immunoblotting, Immunoprecipitation, Molecular Sequence Data, Mutation, Phosphorylation, Protein Binding, Protein Biosynthesis, Protein Structure, Tertiary, S Phase, Time Factors, Transcription, Genetic, Transcriptional Activation.
Abstract
Deregulation of the cell cycle is a common strategy employed by many DNA and RNA viruses to trap and exploit the host cell machinery toward their own benefit. In many coronaviruses, the nucleocapsid protein (N protein) has been shown to inhibit cell cycle progression although the mechanism behind this is poorly understood. The N protein of severe acute respiratory syndrome-coronavirus (SARS-CoV) bears signature motifs for binding to cyclin and phosphorylation by cyclin-dependent kinase (CDK) and has recently been reported by us to get phosphorylated by the cyclin-CDK complex (Surjit, M., Kumar, R., Mishra, R. N., Reddy, M. K., Chow, V. T., and Lal, S. K. (2005) J. Virol. 79, 11476-11486). In the present study, we prove that the N protein of SARS-CoV can inhibit S phase progression in mammalian cell lines. N protein expression was found to directly inhibit the activity of the cyclin-CDK complex, resulting in hypophosphorylation of retinoblastoma protein with a concomitant down-regulation in E2F1-mediated transactivation. Coexpression of E2F1 under such conditions could restore the expression of S phase genes. Analysis of RXL and CDK phosphorylation mutant N protein identified the mechanism of inhibition of CDK4 and CDK2 activity to be different. Whereas N protein could directly bind to cyclin D and inhibit the activity of CDK4-cyclin D complex; inhibition of CDK2 activity appeared to be achieved in two different ways: indirectly by down-regulation of protein levels of CDK2, cyclin E, and cyclin A and by direct binding of N protein to CDK2-cyclin complex. Down-regulation of E2F1 targets was also observed in SARS-CoV-infected VeroE6 cells. These data suggest that the S phase inhibitory activity of the N protein may have major significance during viral pathogenesis.
DOI: 10.1074/jbc.M509233200
PubMed: 16431923
Affiliations:
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Le document en format XML
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Chow</name></author><author><name sortKey="Lal, Sunil K" sort="Lal, Sunil K" uniqKey="Lal S" first="Sunil K" last="Lal">Sunil K. Lal</name></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="ISSN">0021-9258</idno><imprint><date when="2006" type="published">2006</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Base Sequence</term><term>Bromodeoxyuridine (pharmacology)</term><term>COS Cells</term><term>Cell Cycle</term><term>Cell Line</term><term>Cell Separation</term><term>Chloramphenicol O-Acetyltransferase (metabolism)</term><term>Chlorocebus aethiops</term><term>Cyclin A (metabolism)</term><term>Cyclin E (metabolism)</term><term>Cyclin-Dependent Kinase 2 (metabolism)</term><term>Cyclin-Dependent Kinases (metabolism)</term><term>Dose-Response Relationship, Drug</term><term>Down-Regulation</term><term>E2F1 Transcription Factor (metabolism)</term><term>Electrophoresis, Polyacrylamide Gel</term><term>Flow Cytometry</term><term>Immunoblotting</term><term>Immunoprecipitation</term><term>Molecular Sequence Data</term><term>Mutation</term><term>Nucleocapsid Proteins (physiology)</term><term>Phosphorylation</term><term>Plasmids (metabolism)</term><term>Protein Binding</term><term>Protein Biosynthesis</term><term>Protein Structure, Tertiary</term><term>Retinoblastoma Protein (metabolism)</term><term>S Phase</term><term>Time Factors</term><term>Transcription, Genetic</term><term>Transcriptional Activation</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Activation de la transcription</term><term>Animaux</term><term>Biosynthèse des protéines</term><term>Broxuridine (pharmacologie)</term><term>Cellules COS</term><term>Chloramphenicol O-acetyltransferase (métabolisme)</term><term>Cycle cellulaire</term><term>Cycline A (métabolisme)</term><term>Cycline E (métabolisme)</term><term>Cytométrie en flux</term><term>Données de séquences moléculaires</term><term>Facteur de transcription E2F1 (métabolisme)</term><term>Facteurs temps</term><term>Immunoprécipitation</term><term>Immunotransfert</term><term>Kinase-2 cycline-dépendante (métabolisme)</term><term>Kinases cyclines-dépendantes (métabolisme)</term><term>Liaison aux protéines</term><term>Lignée cellulaire</term><term>Mutation</term><term>Phase S</term><term>Phosphorylation</term><term>Plasmides (métabolisme)</term><term>Protéine du rétinoblastome (métabolisme)</term><term>Protéines nucléocapside (physiologie)</term><term>Relation dose-effet des médicaments</term><term>Régulation négative</term><term>Structure tertiaire des protéines</term><term>Séparation cellulaire</term><term>Séquence nucléotidique</term><term>Transcription génétique</term><term>Électrophorèse sur gel de polyacrylamide</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Chloramphenicol O-Acetyltransferase</term><term>Cyclin A</term><term>Cyclin E</term><term>Cyclin-Dependent Kinase 2</term><term>Cyclin-Dependent Kinases</term><term>E2F1 Transcription Factor</term><term>Retinoblastoma Protein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Bromodeoxyuridine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Nucleocapsid Proteins</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Plasmids</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Chloramphenicol O-acetyltransferase</term><term>Cycline A</term><term>Cycline E</term><term>Facteur de transcription E2F1</term><term>Kinase-2 cycline-dépendante</term><term>Kinases cyclines-dépendantes</term><term>Plasmides</term><term>Protéine du rétinoblastome</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Broxuridine</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Protéines nucléocapside</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Base Sequence</term><term>COS Cells</term><term>Cell Cycle</term><term>Cell Line</term><term>Cell Separation</term><term>Chlorocebus aethiops</term><term>Dose-Response Relationship, Drug</term><term>Down-Regulation</term><term>Electrophoresis, Polyacrylamide Gel</term><term>Flow Cytometry</term><term>Immunoblotting</term><term>Immunoprecipitation</term><term>Molecular Sequence Data</term><term>Mutation</term><term>Phosphorylation</term><term>Protein Binding</term><term>Protein Biosynthesis</term><term>Protein Structure, Tertiary</term><term>S Phase</term><term>Time Factors</term><term>Transcription, Genetic</term><term>Transcriptional Activation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Activation de la transcription</term><term>Animaux</term><term>Biosynthèse des protéines</term><term>Cellules COS</term><term>Cycle cellulaire</term><term>Cytométrie en flux</term><term>Données de séquences moléculaires</term><term>Facteurs temps</term><term>Immunoprécipitation</term><term>Immunotransfert</term><term>Liaison aux protéines</term><term>Lignée cellulaire</term><term>Mutation</term><term>Phase S</term><term>Phosphorylation</term><term>Relation dose-effet des médicaments</term><term>Régulation négative</term><term>Structure tertiaire des protéines</term><term>Séparation cellulaire</term><term>Séquence nucléotidique</term><term>Transcription génétique</term><term>Électrophorèse sur gel de polyacrylamide</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Deregulation of the cell cycle is a common strategy employed by many DNA and RNA viruses to trap and exploit the host cell machinery toward their own benefit. In many coronaviruses, the nucleocapsid protein (N protein) has been shown to inhibit cell cycle progression although the mechanism behind this is poorly understood. The N protein of severe acute respiratory syndrome-coronavirus (SARS-CoV) bears signature motifs for binding to cyclin and phosphorylation by cyclin-dependent kinase (CDK) and has recently been reported by us to get phosphorylated by the cyclin-CDK complex (Surjit, M., Kumar, R., Mishra, R. N., Reddy, M. K., Chow, V. T., and Lal, S. K. (2005) J. Virol. 79, 11476-11486). In the present study, we prove that the N protein of SARS-CoV can inhibit S phase progression in mammalian cell lines. N protein expression was found to directly inhibit the activity of the cyclin-CDK complex, resulting in hypophosphorylation of retinoblastoma protein with a concomitant down-regulation in E2F1-mediated transactivation. Coexpression of E2F1 under such conditions could restore the expression of S phase genes. Analysis of RXL and CDK phosphorylation mutant N protein identified the mechanism of inhibition of CDK4 and CDK2 activity to be different. Whereas N protein could directly bind to cyclin D and inhibit the activity of CDK4-cyclin D complex; inhibition of CDK2 activity appeared to be achieved in two different ways: indirectly by down-regulation of protein levels of CDK2, cyclin E, and cyclin A and by direct binding of N protein to CDK2-cyclin complex. Down-regulation of E2F1 targets was also observed in SARS-CoV-infected VeroE6 cells. These data suggest that the S phase inhibitory activity of the N protein may have major significance during viral pathogenesis.</div></front></TEI><affiliations><list><country><li>Inde</li></country></list><tree><noCountry><name sortKey="Chow, Vincent T K" sort="Chow, Vincent T K" uniqKey="Chow V" first="Vincent T K" last="Chow">Vincent T K. Chow</name><name sortKey="Lal, Sunil K" sort="Lal, Sunil K" uniqKey="Lal S" first="Sunil K" last="Lal">Sunil K. Lal</name><name sortKey="Liu, Boping" sort="Liu, Boping" uniqKey="Liu B" first="Boping" last="Liu">Boping Liu</name></noCountry><country name="Inde"><noRegion><name sortKey="Surjit, Milan" sort="Surjit, Milan" uniqKey="Surjit M" first="Milan" last="Surjit">Milan Surjit</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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