title: Tamoxifen inhibits CDK5 kinase activity by interacting with p35/p25 and modulates the pattern of tau phosphorylation.
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.
authors: 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.
authors: Caroline
authors: C
authors: Corbel
authors: School of Renewable Energy, North China Electric Power Electricity, 071003 Beijing, China.
authors: Bing
authors: B
authors: Zhang
authors: EA4250-LIMATB-EG2B, Centre de Recherche et d'Enseignement Yves Coppens, Université de Bretagne Sud, 56017 Vannes, France.
authors: Annabelle
authors: A
authors: Le Parc
authors: USR3151-CNRS/UPMC, Protein Phosphorylation and Disease Laboratory, Station Biologique de Roscoff, CS 90074, 29688 Roscoff, Bretagne, France.
authors: Blandine
authors: B
authors: Baratte
authors: USR3151-CNRS/UPMC, Protein Phosphorylation and Disease Laboratory, Station Biologique de Roscoff, CS 90074, 29688 Roscoff, Bretagne, France.
authors: Pierre
authors: P
authors: Colas
authors: UMR761-INSERM Lille University, Biostructures and Drug Discovery, 59006 Lille, France.
authors: Cyril
authors: C
authors: Couturier
authors: Kosik Laboratory, Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
authors: Kenneth S
authors: KS
authors: Kosik
authors: UMR8576 CNRS-Lille North of France University, 59658 Villeneuve d'Ascq, France; Interdisciplinary Research Institute (IRI), 58658 Villeneuve d'Ascq, France.
authors: Isabelle
authors: I
authors: Landrieu
authors: EA4250-LIMATB-EG2B, Centre de Recherche et d'Enseignement Yves Coppens, Université de Bretagne Sud, 56017 Vannes, France.
authors: Véronique
authors: V
authors: Le Tilly
authors: USR3151-CNRS/UPMC, Protein Phosphorylation and Disease Laboratory, Station Biologique de Roscoff, CS 90074, 29688 Roscoff, Bretagne, France. Electronic address: bach@sb-roscoff.fr.
authors: Stéphane
authors: S
authors: Bach
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D062105:Molecular Docking Simulation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000737:chemistry / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C500695:CDCA5 protein, human; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; C118136:TPPP protein, human; D016875:tau Proteins; D013629:Tamoxifen; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human