Selective cell-cycle arrest and induction of apoptosis in proliferating neural cells by ganglioside GM3.
Control of cell proliferation and cell survival is critical during development of the vertebrate central nervous system (CNS). Much of the cell death seen during early stages of CNS development occurs through apoptosis; however, the factors that induce this early apoptosis are not clearly understood. Gangliosides, sialylated glycosphingolipids, are expressed in the CNS and have been proposed to regulate cell growth and differentiation. Here we show that the simple ganglioside GM3 selectively inhibits the proliferation of and induces apoptosis of actively dividing astrocyte precursors and other neural progenitors. The inhibition of astrocyte precursor proliferation by GM3 appears to be mediated in part by the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1). During neonatal development there is extensive cell proliferation and little apoptosis in the ventricular and subventricular zones of the CNS. This proliferation was dramatically inhibited and the degree of apoptosis dramatically increased following intraventricular administration of GM3. These data suggest that GM3, a simple ganglioside, may regulate cell proliferation and death in the CNS and as such may have potential for brain tumor therapy.
Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
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Nakatsuji
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Miller
D016475:3T3 Cells; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005679:G(M3) Ganglioside / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D005679:G(M3) Ganglioside