title: Schizophrenia susceptibility gene product dysbindin-1 regulates the homeostasis of cyclin D1.
abstract: Dysbindin-1 (dystrobrevin binding protein-1, DTNBP1) is now widely accepted as a potential schizophrenia susceptibility gene and accumulating evidence indicates its functions in the neural development. In this study, we tried to identify new binding partners for dysbindin-1 to clarify the novel function of this molecule. When consulted with BioGRID protein interaction database, cyclin D3 was found to be a possible binding partner for dysbindin-1. We then examined the interaction between various dysbindin-1 isoforms (dysbindin-1A, -1B and -1C) and all three D-type cyclins (cyclin D1, D2, and D3) by immunoprecipitation with the COS7 cell expression system, and found that dysbindin-1A preferentially interacts with cyclin D1. The mode of interaction between these molecules was considered as direct binding since recombinant dysbindin-1A and cyclin D1 formed a complex in vitro. Mapping analyses revealed that the C-terminal region of dysbindin-1A binds to the C-terminal of cyclin D1. Consistent with the results of the biochemical analyses, endogenous dysbindin-1was partially colocalized with cyclin D1 in NIH3T3 fibroblast cells and in neuronal stem and/or progenitor cells in embryonic mouse brain. While co-expression of dysbindin-1A with cyclin D1 changed the localization of the latter from the nucleus to cytosol, cyclin D1-binding partner CDK4 inhibited the dysbindin-cyclin D1 interaction. Meanwhile, depletion of endogenous dysbindin-1A increased cyclin D1 expression. These results indicate that dysbindin-1A may control the cyclin D1 function spatiotemporally and might contribute to better understanding of the pathophysiology of dysbindin-1-associated disorders.
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Morishita
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan; Department of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: knagata@inst-hsc.jp.
authors.forename: Koh-Ichi
authors.initials: K
authors.lastname: Nagata
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001921:Brain / Q000196:embryology; D019556:COS Cells; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D000074765:Dysbindin / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D058953:Neural Stem Cells / Q000378:metabolism; D000072417:Protein Domains; D012559:Schizophrenia
chemical_list: C530105:Ccnd1 protein, mouse; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D019938:Cyclin D1
keywords: Cyclin D1; Dysbindin-1; Schizophrenia