title: Psychosine-triggered endomitosis is modulated by membrane sphingolipids through regulation of phosphoinositide 4,5-bisphosphate production at the cleavage furrow.
abstract: Endomitosis is a special type of mitosis in which only cytokinesis-the final step of the cell division cycle-is defective, resulting in polyploid cells. Although endomitosis is biologically important, its regulatory aspects remain elusive. Psychosine, a lysogalactosylceramide, prevents proper cytokinesis when supplemented to proliferating cells. Cytokinetic inhibition by psychosine does not inhibit genome duplication. Consequently cells undergo multiple rounds of endomitotic cell cycles, resulting in the formation of giant multiploid cells. Here we successfully quantified psychosine-triggered multiploid cell formation, showing that membrane sphingolipids ratios modulate psychosine-triggered polyploidy in Namalwa cells. Among enzymes that experimentally remodel cellular sphingolipids, overexpression of glucosylceramide synthase to biosynthesize glycosylsphingolipids (GSLs) and neutral sphingomyelinase 2 to hydrolyze sphingomyelin (SM) additively enhanced psychosine-triggered multiploidy; almost all of the cells became polyploid. In the presence of psychosine, Namalwa cells showed attenuated cell surface SM clustering and suppression of phosphatidylinositol 4,5-bisphosphate production at the cleavage furrow, both important processes for cytokinesis. Depending on the sphingolipid balance between GSLs and SM, Namalwa cells could be effectively converted to viable multiploid cells with psychosine.
authors.affiliation: Laboratory of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Okahara
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Naito-Matsui
authors.affiliation: RIKEN Frontier Research System and RIKEN Advanced Science Institute, Wako 351-0198, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Abe
authors.affiliation: Division of Glycopathology, Institute of Molecular Biomembranes and Glycobiology, Tohoku Pharmaceutical University, Sendai 981-8558, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Go
authors.affiliation: Division of Glycopathology, Institute of Molecular Biomembranes and Glycobiology, Tohoku Pharmaceutical University, Sendai 981-8558, Japan.
authors.forename: Jinichi
authors.initials: J
authors.lastname: Inokuchi
authors.affiliation: Department of Hematology and Immunology, Kanazawa Medical University, Uchinada 920-0293, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Okazaki
authors.affiliation: RIKEN Frontier Research System and RIKEN Advanced Science Institute, Wako 351-0198, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kozutsumi
authors.affiliation: Laboratory of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Oka
authors.affiliation: Laboratory of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan htakema@pharm.kyoto-u.ac.jp.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Takematsu
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002970:Cleavage Stage, Ovum; D048749:Cytokinesis / Q000502:physiology; D005964:Glucosyltransferases; D006801:Humans; D008566:Membranes; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011123:Polyploidy; D011609:Psychosine / Q000378:metabolism* / Q000494:pharmacology; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D010716:Phosphatidylinositols; D013107:Sphingolipids; D011609:Psychosine; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase