A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells.
The unique property of stem cells to self-renew suggests specific mechanisms that regulate their cell-cycle progression. In the present study, we identify a novel protein, nucleostemin, found in the nucleoli of CNS stem cells, embryonic stem cells, and several cancer cell lines and preferentially expressed by other stem cell-enriched populations. It contains an N-terminal basic domain and two GTP-binding motifs. When stem cells differentiate, nucleostemin expression decreases rapidly prior to cell-cycle exit both in vitro and in vivo. Depletion or overexpression of nucleostemin reduces cell proliferation in CNS stem cells and transformed cells. Mutation analysis indicates that excessive nucleostemin, particularly mutants that lack the GTP-regulatory domain, prevents cells from entering mitosis and causes apoptosis in a p53-dependent manner. The N-terminal basic domain specifies nucleolar localization, the p53 interaction, and is required for the cell death caused by overexpression. This work describes a novel nucleolar mechanism that controls the cell-cycle progression in CNS stem cells and cancer cells.
Tsai
Robert Y L
RY
Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
McKay
Ronald D G
RD
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002466:Cell Nucleolus / Q000378:metabolism* / Q000648:ultrastructure; D002490:Central Nervous System / Q000378:metabolism; D003001:Cloning, Molecular; D015536:Down-Regulation; D019204:GTP-Binding Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins; D051381:Rats; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002352:Carrier Proteins; C470310:Gnl3 protein, rat; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C470311:nucleostemin protein, mouse; D019204:GTP-Binding Proteins