title: Translokin (Cep57) interacts with cyclin D1 and prevents its nuclear accumulation in quiescent fibroblasts.
abstract: Nuclear accumulation of cyclin D1 because of altered trafficking or degradation is thought to contribute directly to neoplastic transformation and growth. Mechanisms of cyclin D1 localization in S phase have been studied in detail, but its control during exit from the cell cycle and quiescence is poorly understood. Here we report that translokin (Tlk), a microtubule-associated protein also termed Cep57, interacts with cyclin D1 and controls its nucleocytoplasmic distribution in quiescent cells. Tlk binds to regions of cyclin D1 also involved in binding to cyclin-dependent kinase 4 (Cdk4), and a fraction of cyclin D1 associates to the juxtanuclear Tlk network in the cell. Downregulation of Tlk levels results in undue nuclear accumulation of cyclin D1 and increased Cdk4-dependent phosphorylation of pRB under quiescence conditions. In turn, overexpression of Tlk prevents proper cyclin D1 accumulation in the nucleus of proliferating cells in an interaction-dependent manner, inhibits Cdk4-dependent phosphorylation of pRB and hinders cell cycle progression to S phase. We propose that the Tlk acts as a key negative regulator in the pathway that drives nuclear import of cyclin D1, thus contributing to prevent pRB inactivation and to maintain cellular quiescence.
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, IRBLLEIDA, Universitat de Lleida, Montserrat Roig 2, 25008 Lleida, Catalonia, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Ruiz-Miró
authors.forename: Neus
authors.initials: N
authors.lastname: Colomina
authors.forename: Rita M H
authors.initials: RM
authors.lastname: Fernández
authors.forename: Eloi
authors.initials: E
authors.lastname: Garí
authors.forename: Carme
authors.initials: C
authors.lastname: Gallego
authors.forename: Martí
authors.initials: M
authors.lastname: Aldea
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016160:Retinoblastoma Protein; C482107:Tsp57 protein, mouse; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4