Lithium induces morphological differentiation of mouse neuroblastoma cells.
Neuroblastoma cells are used as a model system to study neuronal differentiation. Here we describe the induction of morphological differentiation of mouse neuroblastoma Neuro 2a (N2a) cells by treatments with either chemical inhibitors of cyclin-dependent kinases or lithium, which inhibits glycogen synthase kinase-3. Cyclin-dependent kinase inhibitors cause a rapid cell cycle block as well as the extension of multiple neurites per cell. These multipolar differentiated cells then undergo a massive death. However, lithium promotes a delayed mitotic arrest and the extension of one or two long neurites per cell. This differentiation is maximal after 48 hours of lithium treatment and the differentiated cells remain viable for long periods of time. Neuronal differentiation in lithium-treated cells is preceded by the accumulation of beta-catenin, a protein which is efficiently proteolyzed when it is phosphorylated by glycogen synthase kinase-3. Both neuronal differentiation and beta-catenin accumulation are observed in lithium-treated cells either in the absence or in the presence of supraphysiological concentrations of inositol. The results are consistent with the hypothesis that inhibition of glycogen synthase kinase-3 by lithium triggers the differentiation of neuroblastoma N2a cells.
Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba.
J
J
García-Pérez
J
J
Avila
J
J
Díaz-Nido
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D008094:Lithium / Q000494:pharmacology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016501:Neurites / Q000502:physiology; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D010766:Phosphorylation; D015534:Trans-Activators; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; D015534:Trans-Activators; D051176:beta Catenin; C085284:microtubule-associated protein 1B; D008094:Lithium; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3