The Nucleolus pp 301-320 | Cite as

New Frontiers in Nucleolar Research: Nucleostemin and Related Proteins

Chapter
Part of the Protein Reviews book series (PRON, volume 15)

Abstract

Nucleostemin, guanine nucleotide binding protein-like 3-like (GNL3L), and Ngp-1 (also known as GNL-2) constitute a novel family of nucleolar GTP-binding proteins that are uniquely defined by the combination of five circularly permuted GTP-binding (G) motifs and nucleolar localization. These proteins elegantly reveal the versatility of the nucleolus. The most well-known member of this family is nucleostemin, which was first identified as a neural stem cell-enriched gene product and has later become a focus of attention in multiple research areas, including cell cycle regulation, telomere maintenance, stem cell biology, tumorigenesis, and tissue regeneration. It has also been used to illustrate the molecular mechanism that controls the dynamic shuttling behavior of nucleolar proteins between the nucleolar and nucleoplasmic compartments. New reports have come out that describe not only the biological importance of nucleostemin in mammals but also the functions of its vertebrate paralog, GNL3L, and their common invertebrate ortholog, GNL3. Current data indicate that nucleostemin and GNL3L may have diverged at the inception of vertebrate evolution, and that nucleostemin may have adopted new biological roles while GNL3L inherited the evolutionarily conserved function of GNL3. In vertebrates, nucleostemin, GNL3L, and Ngp-1 display distinct expression profiles and biological activities. They cogently illustrate the complexity of nucleolar biology by showing how this classic organelle integrates a variety of extra- and intra-cellular signals to control key biological events in a dynamic and cell type-specific manner.

Keywords

Estrogen Luminal Arena Guanine Ligase 

References

  1. Baddoo M, Hill K, Wilkinson R, Gaupp D, Hughes C, Kopen GC, Phinney DG (2003) Characterization of mesenchymal stem cells isolated from murine bone marrow by negative selection. J Cell Biochem 89:1235–1249PubMedCrossRefGoogle Scholar
  2. Barrientos A, Korr D, Barwell KJ, Sjulsen C, Gajewski CD, Manfredi G, Ackerman S, Tzagoloff A (2003) MTG1 codes for a conserved protein required for mitochondrial translation. Mol Biol Cell 14:2292–2302PubMedCrossRefGoogle Scholar
  3. Bassler J, Grandi P, Gadal O, Lessmann T, Petfalski E, Tollervey D, Lechner J, Hurt E (2001) Identification of a 60S preribosomal particle that is closely linked to nuclear export. Mol Cell 8:517–529PubMedCrossRefGoogle Scholar
  4. Beekman C, Nichane M, De Clercq S, Maetens M, Floss T, Wurst W, Bellefroid E, Marine JC (2006) Evolutionarily Conserved Role of Nucleostemin: Controlling Proliferation of Stem/Progenitor Cells during Early Vertebrate Development. Mol Cell Biol 26:9291–9301PubMedCrossRefGoogle Scholar
  5. Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP (2004) PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol 6:665–672PubMedCrossRefGoogle Scholar
  6. Charpentier AH, Bednarek AK, Daniel RL, Hawkins KA, Laflin KJ, Gaddis S, MacLeod MC, Aldaz CM (2000) Effects of estrogen on global gene expression: identification of novel targets of estrogen action. Cancer Res 60:5977–5983PubMedGoogle Scholar
  7. Chen D, Huang S (2001) Nucleolar components involved in ribosome biogenesis cycle between the nucleolus and nucleoplasm in interphase cells. J Cell Biol 153:169–176PubMedCrossRefGoogle Scholar
  8. Dai MS, Zeng SX, Jin Y, Sun XX, David L, Lu H (2004) Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol Cell Biol 24:7654–7668PubMedCrossRefGoogle Scholar
  9. Dai MS, Sun XX, Lu H (2008) Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2. Mol Cell Biol 28:4365–4376PubMedCrossRefGoogle Scholar
  10. Daigle DM, Rossi L, Berghuis AM, Aravind L, Koonin EV, Brown ED (2002) YjeQ, an essential, conserved, uncharacterized protein from Escherichia coli, is an unusual GTPase with circularly permuted G-motifs and marked burst kinetics. Biochemistry 41:11109–11117PubMedCrossRefGoogle Scholar
  11. Du X, Rao MR, Chen XQ, Wu W, Mahalingam S, Balasundaram D (2006) The homologous putative GTPases Grn1p from fission yeast and the human GNL3L are required for growth and play a role in processing of nucleolar pre-rRNA. Mol Biol Cell 17:460–474PubMedCrossRefGoogle Scholar
  12. Fu D, Collins K (2007) Purification of human telomerase complexes identifies factors involved in telomerase biogenesis and telomere length regulation. Mol Cell 28:773–785PubMedCrossRefGoogle Scholar
  13. Huang M, Itahana K, Zhang Y, Mitchell BS (2009) Depletion of guanine nucleotides leads to the Mdm2-dependent proteasomal degradation of nucleostemin. Cancer Res 69:3004–3012PubMedCrossRefGoogle Scholar
  14. Jafarnejad SM, Mowla SJ, Matin MM (2008) Knocking-down the expression of nucleostemin significantly decreases rate of proliferation of rat bone marrow stromal stem cells in an apparently p53-independent manner. Cell Prolif 41:28–35PubMedCrossRefGoogle Scholar
  15. Jin A, Itahana K, O’Keefe K, Zhang Y (2004) Inhibition of HDM2 and activation of p53 by ribosomal protein L23. Mol Cell Biol 24:7669–7680PubMedCrossRefGoogle Scholar
  16. Kafienah W, Mistry S, Williams C, Hollander AP (2006) Nucleostemin is a marker of proliferating stromal stem cells in adult human bone marrow. Stem Cells 24:1113–1120PubMedCrossRefGoogle Scholar
  17. Kallstrom G, Hedges J, Johnson A (2003) The putative GTPases Nog1p and Lsg1p are required for 60S ribosomal subunit biogenesis and are localized to the nucleus and cytoplasm, respectively. Mol Cell Biol 23:4344–4355PubMedCrossRefGoogle Scholar
  18. Kaplan DD, Zimmermann G, Suyama K, Meyer T, Scott MP (2008) A nucleostemin family GTPase, NS3, acts in serotonergic neurons to regulate insulin signaling and control body size. Genes Dev 22:1877–1893PubMedCrossRefGoogle Scholar
  19. Kudron MM, Reinke V (2008) C. elegans nucleostemin is required for larval growth and germline stem cell division. PLoS Genet 4:e1000181PubMedCrossRefGoogle Scholar
  20. Kurki S, Peltonen K, Latonen L, Kiviharju TM, Ojala PM, Meek D, Laiho M (2004) Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 5:465–475PubMedCrossRefGoogle Scholar
  21. Leipe DD, Wolf YI, Koonin EV, Aravind L (2002) Classification and evolution of P-loop GTPases and related ATPases. J Mol Biol 317:41–72PubMedCrossRefGoogle Scholar
  22. Lin T, Meng L, Li Y, Tsai RY (2010) Tumor-initiating function of nucleostemin-enriched mammary tumor cells. Cancer Res 70:9444–9452PubMedCrossRefGoogle Scholar
  23. Liu SJ, Cai ZW, Liu YJ, Dong MY, Sun LQ, Hu GF, Wei YY, Lao WD (2004) Role of nucleostemin in growth regulation of gastric cancer, liver cancer and other malignancies. World J Gastroenterol 10:1246–1249PubMedGoogle Scholar
  24. Ma H, Pederson T (2007) Depletion of the nucleolar protein nucleostemin causes G1 cell cycle arrest via the p53 pathway. Mol Biol Cell 18:2630–2635PubMedCrossRefGoogle Scholar
  25. Ma H, Pederson T (2008) Nucleophosmin is a binding partner of nucleostemin in human osteosarcoma cells. Mol Biol Cell 19:2870–2875PubMedCrossRefGoogle Scholar
  26. Ma L, Chang N, Guo S, Li Q, Zhang Z, Wang W, Tong T (2008) CSIG inhibits PTEN translation in replicative senescence. Mol Cell Biol 28:6290–6301PubMedCrossRefGoogle Scholar
  27. Maki N, Takechi K, Sano S, Tarui H, Sasai Y, Agata K (2007) Rapid accumulation of nucleostemin in nucleolus during newt regeneration. Dev Dyn 236:941–950PubMedCrossRefGoogle Scholar
  28. Matsuo E, Kanno S, Matsumoto S, Tsuneizumi K (2010) Drosophila nucleostemin 2 proved essential for early eye development and cell survival. Biosci Biotechnol Biochem 74:2120–2123Google Scholar
  29. McMahon FJ, Akula N, Schulze TG, Muglia P, Tozzi F, Detera-Wadleigh SD, Steele CJ, Breuer R, Strohmaier J, Wendland JR, Mattheisen M, Muhleisen TW, Maier W, Nothen MM, Cichon S, Farmer A, Vincent JB, Holsboer F, Preisig M, Rietschel M (2010) Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1. Nat Genet 42:128–131PubMedCrossRefGoogle Scholar
  30. Mekhail K, Gunaratnam L, Bonicalzi ME, Lee S (2004) HIF activation by pH-dependent nucleolar sequestration of VHL. Nat Cell Biol 6:642–647PubMedCrossRefGoogle Scholar
  31. Meng L, Yasumoto H, Tsai RY (2006) Multiple controls regulate nucleostemin partitioning between nucleolus and nucleoplasm. J Cell Sci 119:5124–5136PubMedCrossRefGoogle Scholar
  32. Meng L, Zhu Q, Tsai RY (2007) Nucleolar trafficking of nucleostemin family proteins: common versus protein-specific mechanisms. Mol Cell Biol 27:8670–8682PubMedCrossRefGoogle Scholar
  33. Meng L, Lin T, Tsai RY (2008) Nucloplasmic mobilization of nucleostemin stabilizes MDM2 and promotes G2-M progression and cell survival. J Cell Sci 121:4037–4046PubMedCrossRefGoogle Scholar
  34. Meng L, Hsu JK, Tsai RY (2010) NL3L depletion destabilizes MDM2 and induces p53-dependent G2/M arrest. Oncogene 30:1716–1726Google Scholar
  35. Misteli T (2005) Going in GTP cycles in the nucleolus. J Cell Biol 168:177–178PubMedCrossRefGoogle Scholar
  36. Nikpour P, Mowla SJ, Jafarnejad SM, Fischer U, Schulz WA (2009) Differential effects of Nucleostemin suppression on cell cycle arrest and apoptosis in the bladder cancer cell lines 5637 and SW1710. Cell Prolif 42:762–769PubMedCrossRefGoogle Scholar
  37. Ohmura M, Naka K, Hoshii T, Muraguchi T, Shugo H, Tamase A, Uema N, Ooshio T, Arai F, Takubo K, Nagamatsu G, Hamaguchi I, Takagi M, Ishihara M, Sakurada K, Miyaji H, Suda T, Hirao A (2008) Identification of stem cells during prepubertal spermatogenesis via monitoring of nucleostemin promoter activity. Stem Cells 26:3237–3246PubMedCrossRefGoogle Scholar
  38. Pederson T (2001) Protein mobility within the nucleus–what are the right moves? Cell 104:635–638PubMedCrossRefGoogle Scholar
  39. Pederson T, Tsai RY (2009) In search of non-ribosomal nucleolar protein function and regulation. J Cell Biol 184:771–776PubMedCrossRefGoogle Scholar
  40. Phair RD, Misteli T (2000) High mobility of proteins in the mammalian cell nucleus. Nature 404:604–609PubMedCrossRefGoogle Scholar
  41. Politz JC, Polena I, Trask I, Bazett-Jones DP, Pederson T (2005) A nonribosomal landscape in the nucleolus revealed by the stem cell protein nucleostemin. Mol Biol Cell 16:3401–3410PubMedCrossRefGoogle Scholar
  42. Racevskis J, Dill A, Stockert R, Fineberg SA (1996) Cloning of a novel nucleolar guanosine 5’-triphosphate binding protein autoantigen from a breast tumor. Cell Growth Differ 7:271–280PubMedGoogle Scholar
  43. Reynaud EG, Andrade MA, Bonneau F, Ly TB, Knop M, Scheffzek K, Pepperkok R (2005) Human Lsg1 defines a family of essential GTPases that correlates with the evolution of compartmentalization. BMC Biol 3:21PubMedCrossRefGoogle Scholar
  44. Romanova L, Grand A, Zhang L, Rayner S, Katoku-Kikyo N, Kellner S, Kikyo N (2009) Critical role of nucleostemin in pre-rRNA processing. J Biol Chem 284:4968–4977PubMedCrossRefGoogle Scholar
  45. Rosby R, Cui Z, Rogers E, Delivron MA, Robinson VL, Dimario PJ (2009) Knockdown of the Drosophila GTPase, nucleostemin 1, impairs large ribosomal subunit biogenesis, cell growth, and midgut precursor cell maintenance. Mol Biol Cell 20:4424–4434PubMedCrossRefGoogle Scholar
  46. Rubbi CP, Milner J (2000) Non-activated p53 co-localizes with sites of transcription within both the nucleoplasm and the nucleolus. Oncogene 19:85–96PubMedCrossRefGoogle Scholar
  47. Rubbi CP, Milner J (2003) Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. Embo J 22:6068–6077PubMedCrossRefGoogle Scholar
  48. Saveanu C, Bienvenu D, Namane A, Gleizes PE, Gas N, Jacquier A, Fromont-Racine M (2001) Nog2p, a putative GTPase associated with pre-60S subunits and required for late 60S maturation steps. Embo J 20:6475–6484PubMedCrossRefGoogle Scholar
  49. Siddiqi S, Gude N, Hosoda T, Muraski J, Rubio M, Emmanuel G, Fransioli J, Vitale S, Parolin C, D’Amario D, Schaefer E, Kajstura J, Leri A, Anversa P, Sussman MA (2008) Myocardial induction of nucleostemin in response to postnatal growth and pathological challenge. Circ Res 103:89–97PubMedCrossRefGoogle Scholar
  50. Tamase A, Muraguchi T, Naka K, Tanaka S, Kinoshita M, Hoshii T, Ohmura M, Shugo H, Ooshio T, Nakada M, Sawamoto K, Onodera M, Matsumoto K, Oshima M, Asano M, Saya H, Okano H, Suda T, Hamada J, Hirao A (2009) Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin. Proc Natl Acad Sci USA 106:17163–17168PubMedCrossRefGoogle Scholar
  51. Tao W, Levine AJ (1999) P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Proc Natl Acad Sci USA 96:6937–6941PubMedCrossRefGoogle Scholar
  52. Tsai RY, McKay RD (2002) A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev 16:2991–3003PubMedCrossRefGoogle Scholar
  53. Tsai RY, McKay RD (2005) A multistep, GTP-driven mechanism controlling the dynamic cycling of nucleostemin. J Cell Biol 168:179–184PubMedCrossRefGoogle Scholar
  54. Tsai RY, Meng L (2009) Nucleostemin: A latecomer with new tricks. Int J Biochem Cell Biol 41:2122–2124PubMedCrossRefGoogle Scholar
  55. van Steensel B, de Lange T (1997) Control of telomere length by the human telomeric protein TRF1. Nature 385:740–743PubMedCrossRefGoogle Scholar
  56. Vernet C, Ribouchon MT, Chimini G, Pontarotti P (1994) Structure and evolution of a member of a new subfamily of GTP-binding proteins mapping to the human MHC class I region. Mamm Genome 5:100–105PubMedCrossRefGoogle Scholar
  57. Yaghoobi MM, Mowla SJ, Tiraihi T (2005) Nucleostemin, a coordinator of self-renewal, is expressed in rat marrow stromal cells and turns off after induction of neural differentiation. Neurosci Lett 390:81–86PubMedCrossRefGoogle Scholar
  58. Yasumoto H, Meng L, Lin T, Zhu Q, Tsai RY (2007) GNL3L inhibits activity of estrogen-related receptor gamma by competing for coactivator binding. J Cell Sci 120:2532–2543PubMedCrossRefGoogle Scholar
  59. Zhang Y, Wolf GW, Bhat K, Jin A, Allio T, Burkhart WA, Xiong Y (2003) Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol 23:8902–8912PubMedCrossRefGoogle Scholar
  60. Zhu Q, Yasumoto H, Tsai RY (2006) Nucleostemin delays cellular senescence and negatively regulates TRF1 protein stability. Mol Cell Biol 26:9279–9290PubMedCrossRefGoogle Scholar
  61. Zhu Q, Meng L, Hsu JK, Lin T, Teishima J, Tsai RY (2009) GNL3L stabilizes the TRF1 complex and promotes mitotic transition. J Cell Biol 185:827–839PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Center for Cancer and Stem Cell BiologyAlkek Institute of Biosciences and Technology, Texas A&M Health Science CenterHoustonUSA

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