Title :

Tamoxifen Inhibits CDK5 Kinase Activity by Interacting with p35/p25 and Modulates the Pattern of Tau Phosphorylation

Author(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]

Journal title :

Chemistry & Biology

Volume number :

22

Pages :

472-482

Publication date :

2015-04

ISSN :

1074-5521

HAL domain(s) :

Chimie/Chimie théorique et/ou physique

English abstract : [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. ...
Show more >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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

ANR Project :

Biotechnologies et bioressources pour la valorisation des écosystèmes marins planctoniques

Administrative institution(s) :

Université de Lille
CNRS

Collections :

• Médicaments et Molécules pour agir sur les Systèmes Vivants (M2SV) - U1177
• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

RMN et interactions moléculaires

Submission date :

2020-02-12T15:44:57Z
2021-07-13T13:40:46Z