title: Cdk6 contributes to cytoskeletal stability in erythroid cells.
abstract: Mice lacking Cdk6 kinase activity suffer from mild anemia accompanied by elevated numbers of Ter119+cells in the bone marrow. The animals show hardly any alterations in erythroid development, indicating that Cdk6 is not required for proliferation and maturation of erythroid cells. There is also no difference in stress erythropoiesis following hemolysisin vivoHowever,Cdk6-/-erythrocytes have a shortened lifespan and are more sensitive to mechanical stressin vitro, suggesting differences in cytoskeletal architecture. Erythroblasts contain both Cdk4 and Cdk6, while mature erythrocytes apparently lack Cdk4 and their Cdk6 is partly associated with the cytoskeleton. We used mass spectrometry to show that Cdk6 interacts with a number of proteins involved in cytoskeleton organization.Cdk6-/-erythroblasts show impaired F-actin formation and lower levels of gelsolin, which interacts with Cdk6. We also found that Cdk6 regulates the transcription of a panel of genes involved in actin (de-)polymerization.Cdk6-deficient cells are sensitive to drugs that interfere with the cytoskeleton, suggesting that our findings are relevant to the treatment of patients with anemia - and may be relevant to cancer patients treated with the new generation of CDK6 inhibitors.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Uras
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Scheicher
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Karoline
authors.initials: K
authors.lastname: Kollmann
authors.affiliation: VetCORE, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Glösmann
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Prchal-Murphy
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Anca S
authors.initials: AS
authors.lastname: Tigan
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Fux
authors.affiliation: Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Germany.|Molecular Medicine Partnership Unit, University of Heidelberg, Germany.
authors.forename: Sandro
authors.initials: S
authors.lastname: Altamura
authors.affiliation: Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Germany.|Molecular Medicine Partnership Unit, University of Heidelberg, Germany.
authors.forename: Joana
authors.initials: J
authors.lastname: Neves
authors.affiliation: Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Germany.|Molecular Medicine Partnership Unit, University of Heidelberg, Germany.
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, and Tufts Cancer Center, Boston, MA, USA.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Hinds
authors.affiliation: Department of Hematopoiesis, Sanquin Research, Amsterdam, the Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: von Lindern
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria veronika.sexl@vetmeduni.ac.at.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
mesh_terms: D008841:Actin Cytoskeleton; D000199:Actins / Q000378:metabolism; D000740:Anemia; D000818:Animals; D051361:Cyclin-Dependent Kinase 6 / Q000502:physiology*; D003599:Cytoskeleton / Q000648:ultrastructure*; D041905:Erythroid Cells / Q000648:ultrastructure*; D018260:Gelsolin / Q000378:metabolism; D005786:Gene Expression Regulation; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000199:Actins; D018260:Gelsolin; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6