Inhibition of Cytokinesis by a Lipid Metabolite, Psychosine

Abstract

Although a number of cellular components of cytokinesis have been identified, little is known about the detailed mechanisms underlying this process. Here, we report that the lipid metabolite psychosine (galactosylsphingosine), derived from galactosylceramide, induced formation of multinuclear cells from a variety of nonadherent and adherent cells due to inhibition of cytokinesis. When psychosine was added to the human myelomonocyte cell line U937, which was the most sensitive among the cell lines tested, cleavage furrow formed either incompletely or almost completely. However, abnormal contractile movement was detected in which the cellular contents of one of the hemispheres of the contracting cell were transferred into its counterpart. Finally, the cleavage furrow disappeared and cytokinesis was reversed. Psychosine treatment also induced giant clots of actin filaments in the cells that probably consisted of small vacuoles with filamentous structures, suggesting that psychosine affected actin reorganization. These observations could account for the formation of multinuclear globoid cells in the brains of patients with globoid cell leukodystrophy, a neurological disorder characterized by the accumulation of psychosine due to galactosylceramidase deficiency.

Abnormal Expression of the Novel Epidermal Enzyme, Glucosylceramide Deacylase, and the Accumulation of its Enzymatic Reaction Product, Glucosylsphingosine, in the Skin of Patients with Atopic Dermatitis

“…10), in which defects of SMase have been associated and that results in the lipidosis for SM, eliciting an accumulation of SPC (Schmuth et al, 2000), although no data suggest that this SPC accumulation is linked to the expression of an SM deacylase-like enzyme. Another similar relevance of N-deacylase for the generation of psychosine has been reported in globoid cell leukodystrophy or Krabbe's disease (Kanazawa et al, 2000). The primary defect of globoid cell leukodystrophy is a deficiency in galactosylceramidase activity, which leads to the accumulation of galactosylceramide and its metabolic intermediate, galactosylsphingosine.…”

“…The primary defect of globoid cell leukodystrophy is a deficiency in galactosylceramidase activity, which leads to the accumulation of galactosylceramide and its metabolic intermediate, galactosylsphingosine. This was speculated to be produced by deacylation of galactosylceramide (Kanazawa et al, 2000), although there is no evidence for the expression of galactosylceramide deacylase in globoid cell leukodystrophy. Such altered lipid metabolisms associated with genetic defects, which lead to the accumulation of lipid substrates and deacylated metabolic intermediates, strongly suggest the principle that defects of metabolic enzymes might induce corresponding alternative pathways in which those substrates are converted to corresponding lysoforms by deacylation.…”

Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

“…In mammalian cells, longchain bases downstream of 3-KDS have been shown to promote or inhibit cell cycle progression via ERK and JNK kinases (Coroneos et al, 1996;Pyne et al, 1996). The sphingolipid psychosine (galactosylsphingosine) triggers the inhibition and reversal of partially completed cytokinesis, and the induction of multinuclear giant cells associated with a sphingolipid metabolic disease, globoid cell leukodystrophy (Kanazawa et al, 2000). Inhibition of sphingolipid biosynthesis by myriocin also induces multinucleation, possibly by signaling via a downstream serine/threonine kinase SLI2, which is regulated by intracellular sphingolipid levels (Kozutsumi et al, 2002).…”

“…Sphingosine can activate ERK to stimulate mitogenesis and proliferation in glomerular mesaglial cells, whereas ceramide stimulates JNK to suppress growth (Coroneos et al, 1996); in airway smooth muscle cells, by contrast, sphingosine elicits growth arrest via JNK and sphingosine phosphate stimulates DNA synthesis via ERK2 (Pyne et al, 1996). In microglial cells, acumulation of the sphingoid base psychosine uncouples mitotic and cytokinesis events, leading to formation of multinucleate cells (Kanazawa et al, 2000). In addition, ganglioside GM1 and cholesterol-enriched domains in the cleavage furrow of sea urchin eggs help create signaling platforms that containing activated Src and PLC␥, which are essential for cytokinesis (Ng et al, 2005).…”

A cellular machine generating apoptosis-prone aneuploid cells

“…(c) Effect of different cell cycle blockers on the abundance of syncytia with an B2n DNA content. Heterokarya produced as in (a), which is without addition of drugs during the coculture period (control), or syncytia produced in the presence of S phase blockers (1 mM thymidine, Sigma; 5 nM etoposide, Sigma) 15 or G2/M blockers (nocodazol as in (b), 500 nM geldanamycin; 10 mM 17-(allylamino-)-17-demthoxygeldanamycin[17AAG]; 25 mM psychosin, all from Calbiochem) 16 were analyzed for their DNA content and the percentage of syncytia with a DNA content of B2n was blotted (n ¼ 3, means7S.E.M.) Figure 1a) and a normal cell size, as determined by analyses of the forward and side scatters in the cytofluorometer (see below).…”