Tamoxifen Inhibits CDK5 Kinase Activity ...
Type de document :
Article dans une revue scientifique
URL permanente :
Titre :
Tamoxifen Inhibits CDK5 Kinase Activity by Interacting with p35/p25 and Modulates the Pattern of Tau Phosphorylation
Auteur(s) :
Corbel, Caroline [Auteur]
Zhang, Bing [Auteur]
Le Parc, Annabelle [Auteur]
Laboratoire d'Ingénierie des Matériaux de Bretagne [LIMATB]
Baratte, Blandine [Auteur]
Colas, Pierre [Auteur]
Couturier, Cyril [Auteur]
Médicaments et Molécules pour agir sur les Systèmes Vivants (M2SV) - U1177
Kosik, Kenneth S. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Landrieu, Isabelle [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Le Tilly, Véronique [Auteur]
Laboratoire d'Ingénierie des Matériaux de Bretagne [LIMATB]
Bach, Stéphane [Auteur]
Zhang, Bing [Auteur]
Le Parc, Annabelle [Auteur]
Laboratoire d'Ingénierie des Matériaux de Bretagne [LIMATB]
Baratte, Blandine [Auteur]
Colas, Pierre [Auteur]
Couturier, Cyril [Auteur]
Médicaments et Molécules pour agir sur les Systèmes Vivants (M2SV) - U1177
Kosik, Kenneth S. [Auteur]
University of California [Santa Barbara] [UC Santa Barbara]
Landrieu, Isabelle [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Le Tilly, Véronique [Auteur]
Laboratoire d'Ingénierie des Matériaux de Bretagne [LIMATB]
Bach, Stéphane [Auteur]
Titre de la revue :
Chemistry & Biology
Numéro :
22
Pagination :
472-482
Date de publication :
2015-04
ISSN :
1074-5521
Discipline(s) HAL :
Chimie/Chimie théorique et/ou physique
Résumé en anglais : [en]
Cyclin-dependent kinase 5 (CDK5) is a multifunctional enzyme that plays numerous roles, notably in brain development. CDK5 is activated through its association with the activators, p35 and p39, rather than by cyclins. ...
Lire la suite >Cyclin-dependent kinase 5 (CDK5) is a multifunctional enzyme that plays numerous roles, notably in brain development. CDK5 is activated through its association with the activators, p35 and p39, rather than by cyclins. Proteolytic procession of the N-terminal part of its activators has been linked to Alzheimer’s disease and various other neuropathies. The interaction with the proteolytic product p25 prolongs CDK5 activation and modifies the substrate specificity. In order to discover small-molecule inhibitors of the interaction between CDK5 and p25, we have used a bioluminescence resonance energy transfer (BRET)-based screening assay. Among the 1,760 compounds screened, the generic drug tamoxifen has been identified. The inhibition of the CDK5 activity by tamoxifen was notably validated by monitoring the phosphorylation state of tau protein. The study of the molecular mechanism of inhibition indicates that tamoxifen interacts with p25 to block the CDK5/p25 interaction and pave the way for new treatments of tauopathies.Lire moins >
Lire la suite >Cyclin-dependent kinase 5 (CDK5) is a multifunctional enzyme that plays numerous roles, notably in brain development. CDK5 is activated through its association with the activators, p35 and p39, rather than by cyclins. Proteolytic procession of the N-terminal part of its activators has been linked to Alzheimer’s disease and various other neuropathies. The interaction with the proteolytic product p25 prolongs CDK5 activation and modifies the substrate specificity. In order to discover small-molecule inhibitors of the interaction between CDK5 and p25, we have used a bioluminescence resonance energy transfer (BRET)-based screening assay. Among the 1,760 compounds screened, the generic drug tamoxifen has been identified. The inhibition of the CDK5 activity by tamoxifen was notably validated by monitoring the phosphorylation state of tau protein. The study of the molecular mechanism of inhibition indicates that tamoxifen interacts with p25 to block the CDK5/p25 interaction and pave the way for new treatments of tauopathies.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Projet ANR :
Établissement(s) :
Université de Lille
CNRS
CNRS
Collections :
Équipe(s) de recherche :
RMN et interactions moléculaires
Date de dépôt :
2020-02-12T15:44:57Z
2021-07-13T13:40:46Z
2021-07-13T13:40:46Z