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Genes & Dev. 16 (23): 2991-3003

Copyright © 2002 by Cold Spring Harbor Laboratory Press.

Vol. 16, No. 23, pp. 2991-3003, December 1, 2002

RESEARCH PAPER
A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells

Robert Y.L. Tsai, and Ronald D.G. McKay1

Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA

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.

[Key Words: Stem cell; nucleostemin; nucleolus; GTP; cell proliferation; p53]


1 Corresponding author.


GENES & DEVELOPMENT 16:2991-3003 © 2002 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/02 $5.00


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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Bassler, M. Kallas, and E. Hurt (2006)
J. Biol. Chem. 281, 24737-24744
   Abstract »    Full Text »    PDF »
Condensin I recruitment and uneven chromatin condensation precede mitotic cell death in response to DNA damage.
M. Blank, Y. Lerenthal, L. Mittelman, and Y. Shiloh (2006)
J. Cell Biol. 174, 195-206
   Abstract »    Full Text »    PDF »
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X. Du, M. R.K. S. Rao, X. Q. Chen, W. Wu, S. Mahalingam, and D. Balasundaram (2006)
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   Abstract »    Full Text »    PDF »
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S. Yaccoby (2005)
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   Abstract »    Full Text »    PDF »
Id3 Induces Growth Arrest and Caspase-2-Dependent Apoptosis in B Lymphocyte Progenitors.
B. L. Kee (2005)
J. Immunol. 175, 4518-4527
   Abstract »    Full Text »    PDF »
Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation.
I. Nakano, A. A. Paucar, R. Bajpai, J. D. Dougherty, A. Zewail, T. K. Kelly, K. J. Kim, J. Ou, M. Groszer, T. Imura, et al. (2005)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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G. Cronwright, K. Le Blanc, C. Gotherstrom, P. Darcy, M. Ehnman, and B. Brodin (2005)
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   Abstract »    Full Text »    PDF »
Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation.
T. Okubo, P. S. Knoepfler, R. N. Eisenman, and B. L. M. Hogan (2005)
Development 132, 1363-1374
   Abstract »    Full Text »    PDF »
Going in GTP cycles in the nucleolus.
T. Misteli (2005)
J. Cell Biol. 168, 177-178
   Abstract »    Full Text »    PDF »
A multistep, GTP-driven mechanism controlling the dynamic cycling of nucleostemin.
R. Y.L. Tsai and R. D.G. McKay (2005)
J. Cell Biol. 168, 179-184
   Abstract »    Full Text »    PDF »
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M.-S. Dai, S. X. Zeng, Y. Jin, X.-X. Sun, L. David, and H. Lu (2004)
Mol. Cell. Biol. 24, 7654-7668
   Abstract »    Full Text »    PDF »
Nucleolar localization of the human telomeric repeat binding factor 2 (TRF2).
S. Zhang, P. Hemmerich, and F. Grosse (2004)
J. Cell Sci. 117, 3935-3945
   Abstract »    Full Text »    PDF »
The Sox-2 Regulatory Regions Display Their Activities in Two Distinct Types of Multipotent Stem Cells.
S. Miyagi, T. Saito, K.-i. Mizutani, N. Masuyama, Y. Gotoh, A. Iwama, H. Nakauchi, S. Masui, H. Niwa, M. Nishimoto, et al. (2004)
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   Abstract »    Full Text »    PDF »
Regenerative Response in Ischemic Brain Restricted by p21cip1/waf1.
J. Qiu, Y. Takagi, J. Harada, N. Rodrigues, M. A. Moskowitz, D. T. Scadden, and T. Cheng (2004)
J. Exp. Med. 199, 937-945
   Abstract »    Full Text »    PDF »
Down-regulation of RNA Helicase II/Gu Results in the Depletion of 18 and 28 S rRNAs in Xenopus Oocyte.
H. Yang, J. Zhou, R. L. Ochs, D. Henning, R. Jin, and B. C. Valdez (2003)
J. Biol. Chem. 278, 38847-38859
   Abstract »    Full Text »    PDF »
Decreased Mitochondrial Nitric Oxide Synthase Activity and Hydrogen Peroxide Relate Persistent Tumoral Proliferation to Embryonic Behavior.
S. Galli, M. I. Labato, E. Bal de Kier Joffe, M. C. Carreras, and J. J. Poderoso (2003)
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   Abstract »    Full Text »    PDF »

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