Tamoxifen inhibits CDK5 kinase activity by interacting with p35/p25 and modulates the pattern of tau phosphorylation

Caroline Corbel; Bing Zhang; Annabelle Le Parc; Blandine Baratte; Pierre Colas; Cyril Couturier; Kenneth S Kosik; Isabelle Landrieu; Véronique Le Tilly; Stéphane Bach

doi:10.1016/j.chembiol.2015.03.009

Tamoxifen inhibits CDK5 kinase activity by interacting with p35/p25 and modulates the pattern of tau phosphorylation

Chem Biol. 2015 Apr 23;22(4):472-482. doi: 10.1016/j.chembiol.2015.03.009. Epub 2015 Apr 9.

Authors

Affiliations

¹ USR3151-CNRS/UPMC, Protein Phosphorylation and Disease Laboratory, Station Biologique de Roscoff, CS 90074, 29688 Roscoff, Bretagne, France; EA4250-LIMATB-EG2B, Centre de Recherche et d'Enseignement Yves Coppens, Université de Bretagne Sud, 56017 Vannes, France; Kosik Laboratory, Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
² School of Renewable Energy, North China Electric Power Electricity, 071003 Beijing, China.
³ EA4250-LIMATB-EG2B, Centre de Recherche et d'Enseignement Yves Coppens, Université de Bretagne Sud, 56017 Vannes, France.
⁴ USR3151-CNRS/UPMC, Protein Phosphorylation and Disease Laboratory, Station Biologique de Roscoff, CS 90074, 29688 Roscoff, Bretagne, France.
⁵ UMR761-INSERM Lille University, Biostructures and Drug Discovery, 59006 Lille, France.
⁶ Kosik Laboratory, Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
⁷ UMR8576 CNRS-Lille North of France University, 59658 Villeneuve d'Ascq, France; Interdisciplinary Research Institute (IRI), 58658 Villeneuve d'Ascq, France.
⁸ USR3151-CNRS/UPMC, Protein Phosphorylation and Disease Laboratory, Station Biologique de Roscoff, CS 90074, 29688 Roscoff, Bretagne, France. Electronic address: bach@sb-roscoff.fr.

PMID: 25865311
DOI: 10.1016/j.chembiol.2015.03.009

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / chemistry
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Binding Sites
Cell Cycle Proteins / chemistry
Cell Cycle Proteins / metabolism*
Cells, Cultured
Cyclin-Dependent Kinase 5 / antagonists & inhibitors*
Cyclin-Dependent Kinase 5 / metabolism
Fluorescence Resonance Energy Transfer
Humans
Molecular Docking Simulation
Nerve Tissue Proteins / chemistry
Nerve Tissue Proteins / metabolism*
Neurons / cytology
Neurons / metabolism
Phosphorylation
Protein Binding
Protein Interaction Domains and Motifs
Rats
Rats, Sprague-Dawley
Tamoxifen / chemistry
Tamoxifen / metabolism*
tau Proteins / metabolism*

Substances

Adaptor Proteins, Signal Transducing
CDCA5 protein, human
Cell Cycle Proteins
Nerve Tissue Proteins
TPPP protein, human
tau Proteins
Tamoxifen
Cyclin-Dependent Kinase 5
CDK5 protein, human