title: A novel crosstalk between calcium/calmodulin kinases II and IV regulates cell proliferation in myeloid leukemia cells.
abstract: CaMKs link transient increases in intracellular Ca(2+) with biological processes. In myeloid leukemia cells, CaMKII, activated by the bcr-abl oncogene, promotes cell proliferation. Inhibition of CaMKII activity restricts cell proliferation, and correlates with growth arrest and differentiation. The mechanism by which the inhibition of CaMKII results in growth arrest and differentiation in myeloid leukemia cells is still unknown. We report that inhibition of CaMKII activity results in an upregulation of CaMKIV mRNA and protein in leukemia cell lines. Conversely, expression of CaMKIV inhibits autophosphorylation and activation of CaMKII, and elicits G0/G1cell cycle arrest,impairing cell proliferation. Furthermore, U937 cells expressing CaMKIV show elevated levels of Cdk inhibitors p27(kip1) and p16(ink4a) and reduced levels of cyclins A, B1 and D1. These findings were also confirmed in the K562 leukemic cell line. The relationship between CaMKII and CaMKIV is also observed in primary acute myeloid leukemia (AML) cells, and it correlates with their immunophenotypic profile. Indeed, immature MO/M1 AML showed increased CaMKIV expression and decreased pCaMKII, whereas highly differentiated M4/M5 AML showed decreased CaMKIV expression and increased pCaMKII levels. Our data reveal a novel cross-talk between CaMKII and CaMKIV and suggest that CaMKII suppresses the expression of CaMKIV to promote leukemia cell proliferation.
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Federico II University, Naples, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Monaco
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Federico II University, Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Rusciano
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Federico II University, Naples, Italy.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Maione
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Federico II University, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Soprano
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Rohini
authors.initials: R
authors.lastname: Gomathinayagam
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Lance R
authors.initials: LR
authors.lastname: Todd
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Salerno, Fisciano, Salerno,Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.affiliation: Instituto di Endocrinologia ed Oncologia Sperimentale, CNR, Naples, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salzano
authors.affiliation: CEINGE-Biotecnologie Avanzate, Italy; Dipartimento di Biochimica e Biotecnologie Mediche, Federico II University, Naples, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Pastore
authors.affiliation: CEINGE-Biotecnologie Avanzate, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Leggiero
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Wilkerson
authors.affiliation: Experimental Pharmacology Unit, Department of Research, National Cancer Institute "Fondazione G. Pascale", Napoli, Italy.
authors.forename: Monia
authors.initials: M
authors.lastname: Rocco
authors.affiliation: Hematology Unit, Azienda Ospedaliera Universitaria "S. Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Selleri
authors.affiliation: Department of Medicine, University of Salerno, Italy; IRCCS "Multimedica", Milan, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: uma.sankar@louisville.edu.
authors.forename: Uma
authors.initials: U
authors.lastname: Sankar
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Federico II University, Naples, Italy. Electronic address: illario@unina.it.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Illario
mesh_terms: D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019925:Cyclin A / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D016130:Immunophenotyping; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020298:U937 Cells
chemical_list: D019925:Cyclin A; D056744:Cyclin B1; D019941:Cyclin-Dependent Kinase Inhibitor p16; D034741:RNA, Small Interfering; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D002118:Calcium
keywords: CaMK; Calcium; Cell cycle; Proliferation