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NPM1  -  nucleophosmin (nucleolar phosphoprotein...

Homo sapiens

 
 
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Disease relevance of NPM1

 

Psychiatry related information on NPM1

  • Lewis (Cognition 71 (1999) B23) suggested that a parsimonious explanation would be that it is the total number of times a word has been encountered that predicts reaction times [7].
 

High impact information on NPM1

 

Chemical compound and disease context of NPM1

 

Biological context of NPM1

  • The assignment with chromosome banding techniques of the breakpoints of the recurrent translocation t(3;5) which leads to NPM1/MLF1 gene fusion in myeloid malignancies has not been unequivocal [4].
  • Studies of knock-out mice have revealed new aspects regarding NPM1 as a tumor-suppressor gene [5].
  • The Treg phenotype of the affected cells is strictly dependent on NPM/ALK expression and function as demonstrated by transfection of the kinase into BaF3 cells and inhibition of its enzymatic activity and expression in ALK+TCL cells [15].
  • Flow cytometric analysis revealed that wortmannin-treated NPM-ALK-transformed cell lines underwent apoptosis [16].
  • Moreover, we show that NPM is a substrate for the UV-activated protein kinase ATR and inhibits the UV-induced p53 phosphorylation at Ser15 [17].
 

Anatomical context of NPM1

  • These findings identify a mechanism of NPM/ALK-mediated oncogenesis based on induction of the Treg phenotype of the transformed CD4(+) T cells [15].
  • We also showed that a mutant p80 lacking the NPM portion was unable to transform NIH 3T3 cells [18].
  • In agreement, Src-kinase inhibitors or pp60(c-src) siRNA significantly decreased the proliferation rate of NPM-ALK-positive ALCL cell lines [19].
  • Primary murine bone marrow retrovirally transduced with NPM-ALK showed a transformed phenotype that was reversible on treatment with PI 3-kinase inhibitors [16].
  • Our data show that NPM-ALK gene transcripts are identified in a subpopulation of ALCL, almost exclusively in T or null cell in origin, and in rare cases of HD [20].
 

Associations of NPM1 with chemical compounds

 

Physical interactions of NPM1

  • NPM binds to the p53 N terminus and inhibits p53 transcriptional activity by more than 70% [17].
  • NPM interacts with N-terminal fragments of BRCA1 and BARD1 in a manner dependent upon BRCA1-BARD1 heterodimer formation [25].
  • Cellular stress signals liberate ARF from the nucleolus where it is bound to B23/nucleophosmin [26].
  • Sedimentation gradient experiments revealed that NPM-ALK forms in vivo multimeric complexes of approximately 200 kDa or greater that also contain normal NPM [27].
  • However, MNDA did bind the NPM-MLF1 product of the t(3;5) that contains the N-terminal 175 residues of NPM [28].
  • B23 distinctively binds Ebp1 isoforms and regulates cell proliferation and survival through p42 and p48, respectively [29].
 

Enzymatic interactions of NPM1

 

Co-localisations of NPM1

 

Regulatory relationships of NPM1

  • Nucleophosmin regulates the stability and transcriptional activity of p53 [34].
  • Kinase assays demonstrated that recombinant NPM inhibited PKR activation in a dose-dependent manner [30].
  • Together, our results reveal a molecular mechanism of ARF in regulating ribosome biogenesis and cell proliferation via inhibiting B23, and suggest a nucleolar role of ARF in surveillance of oncogenic insults [35].
  • Our results are consistent with the hypothesis that the Ran-Crm1 complex may promote a local enrichment of NPM on centrosomes, thereby preventing centrosome reduplication [36].
  • The present cases of ALCL associated with a novel t(1;2)(q25;p23) demonstrate that at least one fusion partner other than NPM can activate the intracytoplasmic domain of the ALK kinase [37].
  • SENP3 catalyses desumoylation of NPM1-SUMO2 conjugates in vitro and counteracts ARF-induced modification of NPM1 by SUMO2 in vivo [38].
 

Other interactions of NPM1

 

Analytical, diagnostic and therapeutic context of NPM1

  • These results suggest that the NPM1 mutation is not necessarily an early event during leukemogenesis or that leukemia clones with NPM1 mutations are sensitive to chemotherapy [1].
  • Conclusions.-Detection of NPM1 gene mutations may allow dissection of the heterogeneous group of AML with normal karyotype into prognostically different subgroups [40].
  • Overall, 6 (3 T and 3 null) of 49 ALCL and 3 (2 nodular sclerosis and 1 mixed cellularity) of 72 HD showed the presence of NPM-ALK transcripts by RT-PCR [20].
  • Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear compartments [27].
  • Western blotting of one-dimensional and two-dimensional gels showed that the form of nucleophosmin B23 that is up-regulated in melanoma represents a posttranslationally modified form, most likely reflecting enhanced phosphorylation in the tumor-derived cells [41].

References

  1. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Suzuki, T., Kiyoi, H., Ozeki, K., Tomita, A., Yamaji, S., Suzuki, R., Kodera, Y., Miyawaki, S., Asou, N., Kuriyama, K., Yagasaki, F., Shimazaki, C., Akiyama, H., Nishimura, M., Motoji, T., Shinagawa, K., Takeshita, A., Ueda, R., Kinoshita, T., Emi, N., Naoe, T. Blood (2005) [Pubmed]
  2. Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas. Piva, R., Chiarle, R., Manazza, A.D., Taulli, R., Simmons, W., Ambrogio, C., D'Escamard, V., Pellegrino, E., Ponzetto, C., Palestro, G., Inghirami, G. Blood (2006) [Pubmed]
  3. Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Cazzaniga, G., Dell'Oro, M.G., Mecucci, C., Giarin, E., Masetti, R., Rossi, V., Locatelli, F., Martelli, M.F., Basso, G., Pession, A., Biondi, A., Falini, B. Blood (2005) [Pubmed]
  4. Loss of the NPM1 gene in myeloid disorders with chromosome 5 rearrangements. Berger, R., Busson, M., Baranger, L., Hélias, C., Lessard, M., Dastugue, N., Speleman, F. Leukemia (2006) [Pubmed]
  5. Nucleophosmin: A versatile molecule associated with hematological malignancies. Naoe, T., Suzuki, T., Kiyoi, H., Urano, T. Cancer Sci. (2006) [Pubmed]
  6. Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias. Mullighan, C.G., Kennedy, A., Zhou, X., Radtke, I., Phillips, L.A., Shurtleff, S.A., Downing, J.R. Leukemia (2007) [Pubmed]
  7. Re-evaluating age-of-acquisition effects: are they simply cumulative-frequency effects? Lewis, M.B., Gerhand, S., Ellis, H.D. Cognition. (2001) [Pubmed]
  8. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Okuda, M., Horn, H.F., Tarapore, P., Tokuyama, Y., Smulian, A.G., Chan, P.K., Knudsen, E.S., Hofmann, I.A., Snyder, J.D., Bove, K.E., Fukasawa, K. Cell (2000) [Pubmed]
  9. Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Wells, R.A., Catzavelos, C., Kamel-Reid, S. Nat. Genet. (1997) [Pubmed]
  10. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Chiarle, R., Simmons, W.J., Cai, H., Dhall, G., Zamo, A., Raz, R., Karras, J.G., Levy, D.E., Inghirami, G. Nat. Med. (2005) [Pubmed]
  11. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Morris, S.W., Kirstein, M.N., Valentine, M.B., Dittmer, K., Shapiro, D.N., Look, A.T., Saltman, D.L. Science (1995) [Pubmed]
  12. In vitro and ex vivo expression of nucleolar proteins B23 and p120 in benign and malignant epithelial lesions of the prostate. Bocker, T., Bittinger, A., Wieland, W., Buettner, R., Fauser, G., Hofstaedter, F., Rüschoff, J. Mod. Pathol. (1995) [Pubmed]
  13. SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling. Honorat, J.F., Ragab, A., Lamant, L., Delsol, G., Ragab-Thomas, J. Blood (2006) [Pubmed]
  14. Two-dimensional gel electrophoresis analyses identify nucleophosmin as an estrogen regulated protein associated with acquired estrogen-independence in human breast cancer cells. Skaar, T.C., Prasad, S.C., Sharareh, S., Lippman, M.E., Brünner, N., Clarke, R. J. Steroid Biochem. Mol. Biol. (1998) [Pubmed]
  15. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3. Kasprzycka, M., Marzec, M., Liu, X., Zhang, Q., Wasik, M.A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  16. 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]
  17. Nucleophosmin sets a threshold for p53 response to UV radiation. Maiguel, D.A., Jones, L., Chakravarty, D., Yang, C., Carrier, F. Mol. Cell. Biol. (2004) [Pubmed]
  18. Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5). Fujimoto, J., Shiota, M., Iwahara, T., Seki, N., Satoh, H., Mori, S., Yamamoto, T. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  19. Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity. Cussac, D., Greenland, C., Roche, S., Bai, R.Y., Duyster, J., Morris, S.W., Delsol, G., Allouche, M., Payrastre, B. Blood (2004) [Pubmed]
  20. Molecular characterization of the t(2;5) (p23; q35) translocation in anaplastic large cell lymphoma (Ki-1) and Hodgkin's disease. Yee, H.T., Ponzoni, M., Merson, A., Goldstein, M., Scarpa, A., Chilosi, M., Menestrina, F., Pittaluga, S., de Wolf-Peeters, C., Shiota, M., Mori, S., Frizzera, G., Inghirami, G. Blood (1996) [Pubmed]
  21. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Redner, R.L., Rush, E.A., Faas, S., Rudert, W.A., Corey, S.J. Blood (1996) [Pubmed]
  22. Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin. Bonvini, P., Gastaldi, T., Falini, B., Rosolen, A. Cancer Res. (2002) [Pubmed]
  23. B23/nucleophosmin serine 4 phosphorylation mediates mitotic functions of polo-like kinase 1. Zhang, H., Shi, X., Paddon, H., Hampong, M., Dai, W., Pelech, S. J. Biol. Chem. (2004) [Pubmed]
  24. Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation. Liu, H., Tan, B.C., Tseng, K.H., Chuang, C.P., Yeh, C.W., Chen, K.D., Lee, S.C., Yung, B.Y. EMBO Rep. (2007) [Pubmed]
  25. Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase. Sato, K., Hayami, R., Wu, W., Nishikawa, T., Nishikawa, H., Okuda, Y., Ogata, H., Fukuda, M., Ohta, T. J. Biol. Chem. (2004) [Pubmed]
  26. The ARF tumour suppressor. Gallagher, S.J., Kefford, R.F., Rizos, H. Int. J. Biochem. Cell Biol. (2006) [Pubmed]
  27. Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Bischof, D., Pulford, K., Mason, D.Y., Morris, S.W. Mol. Cell. Biol. (1997) [Pubmed]
  28. MNDA binds NPM/B23 and the NPM-MLF1 chimera generated by the t(3;5) associated with myelodysplastic syndrome and acute myeloid leukemia. Xie, J., Briggs, J.A., Morris, S.W., Olson, M.O., Kinney, M.C., Briggs, R.C. Exp. Hematol. (1997) [Pubmed]
  29. Ebp1 association with nucleophosmin/B23 is essential for regulating cell proliferation and suppressing apoptosis. Okada, M., Jang, S.W., Ye, K. J. Biol. Chem. (2007) [Pubmed]
  30. Nucleophosmin interacts with and inhibits the catalytic function of eukaryotic initiation factor 2 kinase PKR. Pang, Q., Christianson, T.A., Koretsky, T., Carlson, H., David, L., Keeble, W., Faulkner, G.R., Speckhart, A., Bagby, G.C. J. Biol. Chem. (2003) [Pubmed]
  31. The RNA binding activity of a ribosome biogenesis factor, nucleophosmin/B23, is modulated by phosphorylation with a cell cycle-dependent kinase and by association with its subtype. Okuwaki, M., Tsujimoto, M., Nagata, K. Mol. Biol. Cell (2002) [Pubmed]
  32. Nucleophosmin is cleaved and inactivated by the cytotoxic granule protease granzyme M during natural killer cell-mediated killing. Cullen, S.P., Afonina, I.S., Donadini, R., Lüthi, A.U., Medema, J.P., Bird, P.I., Martin, S.J. J. Biol. Chem. (2009) [Pubmed]
  33. Effects of anti-PM-Scl 100 (Rrp6p exonuclease) antibodies on prenucleolar body dynamics at the end of mitosis. Fomproix, N., Hernandez-Verdun, D. Exp. Cell Res. (1999) [Pubmed]
  34. Nucleophosmin regulates the stability and transcriptional activity of p53. Colombo, E., Marine, J.C., Danovi, D., Falini, B., Pelicci, P.G. Nat. Cell Biol. (2002) [Pubmed]
  35. Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Itahana, K., Bhat, K.P., Jin, A., Itahana, Y., Hawke, D., Kobayashi, R., Zhang, Y. Mol. Cell (2003) [Pubmed]
  36. Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication. Wang, W., Budhu, A., Forgues, M., Wang, X.W. Nat. Cell Biol. (2005) [Pubmed]
  37. A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. Lamant, L., Dastugue, N., Pulford, K., Delsol, G., Mariamé, B. Blood (1999) [Pubmed]
  38. The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing. Haindl, M., Harasim, T., Eick, D., Muller, S. EMBO Rep. (2008) [Pubmed]
  39. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Morris, S.W., Kirstein, M.N., Valentine, M.B., Dittmer, K.G., Shapiro, D.N., Saltman, D.L., Look, A.T. Science (1994) [Pubmed]
  40. Nucleophosmin gene mutations in acute myeloid leukemia. Chen, W., Rassidakis, G.Z., Medeiros, L.J. Arch. Pathol. Lab. Med. (2006) [Pubmed]
  41. Functional proteomic analysis of melanoma progression. Bernard, K., Litman, E., Fitzpatrick, J.L., Shellman, Y.G., Argast, G., Polvinen, K., Everett, A.D., Fukasawa, K., Norris, D.A., Ahn, N.G., Resing, K.A. Cancer Res. (2003) [Pubmed]
 
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