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Npm1  -  nucleophosmin 1

Mus musculus

Synonyms: B23, NO38, NPM, Npm, Nucleolar phosphoprotein B23, ...
 
 
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Disease relevance of Npm1

  • Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway [1].
  • The NPM gene is the most frequent target of genetic alterations in leukemias and lymphomas, though its role in tumorigenesis is unknown [2].
  • Using a cDNA probe encoding the nucleolar protein NO38 of Xenopus laevis, we have isolated clones that code for the corresponding mammalian protein from cDNA libraries of mouse embryonal carcinoma and fetal liver cells [3].
  • Nucleophosmin: A versatile molecule associated with hematological malignancies [4].
  • Interestingly, HSCs infected with NPM retrovirus show significantly reduced commitment to myeloid differentiation compared with vector-transduced cells, and majority of the NPM-overexpressing cells remains primitive during a 5-day culture [5].
 

High impact information on Npm1

  • Here, we demonstrate that two major nucleolar proteins, nucleolin and NO38, are highly phosphorylated during mitosis [6].
  • The ability to efficiently control shRNA expression by using these vectors was shown in cell-based experiments by knocking down p53, nucleophosmin and DNA methyltransferase 1 [7].
  • Our data demonstrate that NPM regulates DNA integrity and, through Arf, inhibits cell proliferation and are consistent with a putative tumor-suppressive function of NPM [2].
  • Cells null for both p53 and NPM grow faster than control cells and are more susceptible to transformation by activated oncogenes, such as mutated Ras or overexpressed Myc [2].
  • Transfer of the NPM mutation into a p53-null background rescued apoptosis in vivo and fibroblast proliferation in vitro [2].
 

Biological context of Npm1

  • We show that Npm1 inactivation leads to unrestricted centrosome duplication and genomic instability [8].
  • Npm1-/- and Npm1(hy/hy) mutants have aberrant organogenesis and die between embryonic day E11.5 and E16.5 owing to severe anaemia resulting from defects in primitive haematopoiesis [8].
  • In an NIH 3T3 derivative cell line (MT-Arf) engineered to conditionally express an Arf transgene, induced p19(Arf) associates with NPM and colocalizes with it in high-molecular-weight complexes (2 to 5 MDa) [9].
  • Flow cytometric analysis revealed that wortmannin-treated NPM-ALK-transformed cell lines underwent apoptosis [1].
  • Primary murine bone marrow retrovirally transduced with NPM-ALK showed a transformed phenotype that was reversible on treatment with PI 3-kinase inhibitors [1].
 

Anatomical context of Npm1

 

Associations of Npm1 with chemical compounds

  • Our data show that the knock-down of Npm1 expression by this siRNA system was not only highly efficient, but also Tc- dose- and induction time-dependent [12].
  • MEK inhibition and phosphorylation of serine 4 on B23 are two coincident events in mitosis [15].
  • Levels of B23 protein were also elevated in ODC-overexpressing cells compared to normal cells or transgenic cells treated with DFMO [16].
  • Phosphorylation of B23 was also increased in ODC-overexpressing cells, and this increased phosphorylation could be blocked by treatment of the cells with the CK2 kinase inhibitors apigenin or 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) [16].
  • This genetic abnormality leads to the expression of the NPM-ALK fusion protein, which encodes a constitutively active tyrosine kinase that plays a causative role in lymphomagenesis [17].
 

Physical interactions of Npm1

  • The Rev peptide that binds to nucleophosmin/B23 with the highest affinity exhibited the greatest cytotoxicity on Ras-3T3 cells and inhibited tumor growth most effectively in nude mice [18].
 

Regulatory relationships of Npm1

 

Other interactions of Npm1

 

Analytical, diagnostic and therapeutic context of Npm1

References

  1. Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Bai, R.Y., Ouyang, T., Miething, C., Morris, S.W., Peschel, C., Duyster, J. Blood (2000) [Pubmed]
  2. Nucleophosmin is required for DNA integrity and p19Arf protein stability. Colombo, E., Bonetti, P., Lazzerini Denchi, E., Martinelli, P., Zamponi, R., Marine, J.C., Helin, K., Falini, B., Pelicci, P.G. Mol. Cell. Biol. (2005) [Pubmed]
  3. DNA cloning and amino acid sequence determination of a major constituent protein of mammalian nucleoli. Correspondence of the nucleoplasmin-related protein NO38 to mammalian protein B23. Schmidt-Zachmann, M.S., Franke, W.W. Chromosoma (1988) [Pubmed]
  4. Nucleophosmin: A versatile molecule associated with hematological malignancies. Naoe, T., Suzuki, T., Kiyoi, H., Urano, T. Cancer Sci. (2006) [Pubmed]
  5. Nucleophosmin regulates cell cycle progression and stress response in hematopoietic stem/progenitor cells. Li, J., Sejas, D.P., Rani, R., Koretsky, T., Bagby, G.C., Pang, Q. J. Biol. Chem. (2006) [Pubmed]
  6. Identification of major nucleolar proteins as candidate mitotic substrates of cdc2 kinase. Peter, M., Nakagawa, J., Dorée, M., Labbé, J.C., Nigg, E.A. Cell (1990) [Pubmed]
  7. Cre-lox-regulated conditional RNA interference from transgenes. Ventura, A., Meissner, A., Dillon, C.P., McManus, M., Sharp, P.A., Van Parijs, L., Jaenisch, R., Jacks, T. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  8. Role of nucleophosmin in embryonic development and tumorigenesis. Grisendi, S., Bernardi, R., Rossi, M., Cheng, K., Khandker, L., Manova, K., Pandolfi, P.P. Nature (2005) [Pubmed]
  9. Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. Bertwistle, D., Sugimoto, M., Sherr, C.J. Mol. Cell. Biol. (2004) [Pubmed]
  10. Characterization of centrosomal association of nucleophosmin/B23 linked to Crm1 activity. Shinmura, K., Tarapore, P., Tokuyama, Y., George, K.R., Fukasawa, K. FEBS Lett. (2005) [Pubmed]
  11. Increased stability of nucleophosmin/B23 in anti-apoptotic effect of ras during serum deprivation. Chou, C.C., Yung, B.Y. Mol. Pharmacol. (2001) [Pubmed]
  12. Inducible and reversible suppression of Npm1 gene expression using stably integrated small interfering RNA vector in mouse embryonic stem cells. Wang, B.B., Lu, R., Wang, W.C., Jin, Y. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  13. Nucleolar distribution of proteins B23 and nucleolin in mouse preimplantation embryos as visualized by immunoelectron microscopy. Biggiogera, M., Bürki, K., Kaufmann, S.H., Shaper, J.H., Gas, N., Amalric, F., Fakan, S. Development (1990) [Pubmed]
  14. Distribution of nucleolar proteins B23 and nucleolin during mouse spermatogenesis. Biggiogera, M., Kaufmann, S.H., Shaper, J.H., Gas, N., Amalric, F., Fakan, S. Chromosoma (1991) [Pubmed]
  15. MEK inhibition and phosphorylation of serine 4 on B23 are two coincident events in mitosis. Hayne, C., Xiang, X., Luo, Z. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  16. B23 is a downstream target of polyamine-modulated CK2. Lawson, K., Larentowicz, L., Laury-Kleintop, L., Gilmour, S.K. Mol. Cell. Biochem. (2005) [Pubmed]
  17. The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) induces two distinct malignant phenotypes in a murine retroviral transplantation model. Miething, C., Grundler, R., Fend, F., Hoepfl, J., Mugler, C., von Schilling, C., Morris, S.W., Peschel, C., Duyster, J. Oncogene (2003) [Pubmed]
  18. Nucleophosmin/B23-binding peptide inhibits tumor growth and up-regulates transcriptional activity of p53. Chan, H.J., Weng, J.J., Yung, B.Y. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  19. A mammalian in vitro centriole duplication system: evidence for involvement of CDK2/cyclin E and nucleophosmin/B23 in centrosome duplication. Tarapore, P., Okuda, M., Fukasawa, K. Cell Cycle (2002) [Pubmed]
  20. PARP-1 and PARP-2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli. Meder, V.S., Boeglin, M., de Murcia, G., Schreiber, V. J. Cell. Sci. (2005) [Pubmed]
  21. CD2 promoter regulated nucleophosmin-anaplastic lymphoma kinase in transgenic mice causes B lymphoid malignancy. Turner, S.D., Merz, H., Yeung, D., Alexander, D.R. Anticancer Res. (2006) [Pubmed]
  22. Relief of YY1-induced transcriptional repression by protein-protein interaction with the nucleolar phosphoprotein B23. Inouye, C.J., Seto, E. J. Biol. Chem. (1994) [Pubmed]
  23. In vivo and in vitro phosphorylation studies of numatrin, a cell cycle regulated nuclear protein, in insulin-stimulated NIH 3T3 HIR cells. Feuerstein, N., Randazzo, P.A. Exp. Cell Res. (1991) [Pubmed]
 
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