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Gene Review

NCL  -  nucleolin

Homo sapiens

Synonyms: C23, Nucleolin, Protein C23
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Disease relevance of NCL

  • In addition, the data provide a possible explanation for the appearance of nucleolin and PARP-1 autoantibodies in some autoimmune diseases [1].
  • The growth factor midkine (MK) is a cytokine that inhibits the attachment of human immunodeficiency virus particles by a mechanism similar to the nucleolin binding HB-19 pseudopeptide [2].
  • Direct interaction between nucleolin and hepatitis C virus NS5B [3].
  • The growth factor pleiotrophin (PTN) has been reported to bind heparan sulfate and nucleolin, two components of the cell surface implicated in the attachment of HIV-1 particles to cells [4].
  • METHODS: Terminal restriction fragment (TRF) was evaluated in 20 surgically resected hepatocellular carcinoma specimens (HCC), corresponding noncancerous liver tissue specimens (NCL), and in 10 liver tissue specimens with chronic liver diseases devoid of cancer (DOC) [5].

Psychiatry related information on NCL


High impact information on NCL

  • We show that an element within D4Z4 specifically binds a multiprotein complex consisting of YY1, a known transcriptional repressor, HMGB2, an architectural protein, and nucleolin [7].
  • Three classes of proteins were studied: first, wild-type and mutant forms of nucleolin, one of the first shuttling proteins identified; second, artificial nuclear reporter proteins derived from cytoplasmic pyruvate kinase; and third, wild-type and mutant lamins differing in their abilities to be incorporated into the lamina [8].
  • We have now identified two major RNA-binding proteins, nucleolin and YB-1, that specifically bind to the JRE [9].
  • The DNA binding activity of nucleolin is primarily S phase specific, much like the transcription of the E6 and E7 oncoproteins of HPV18 in cervical cancer cells [10].
  • Antisense inactivation of nucleolin blocks E6 and E7 oncogene transcription and selectively decreases HPV18(+) cervical cancer cell growth [10].

Chemical compound and disease context of NCL

  • Consequently, equilibrium density fractionation of extracts from infected cells revealed that HIV proteins and nucleolin copurify with Triton X-100-resistant GEM-associated proteins [11].
  • Taken together, our results suggest that nucleolin, PHAP II, and PHAP I appear to be functional as potential receptors in the HIV binding process by virtue of their capacity to interact with the V3 loop of gp120 [12].
  • TI-23 consists of lyophilized regavirumab (monoclonal antibody C23, MCA C23), a new human monoclonal antibody against cytomegalovirus (CMV), human serum albumin (HSA) and amino acetic acid [13].
  • Membrane localized nucleolin binds heparin-bound growth factors (including HGF) and appears upregulated during prostate cancer progression [14].

Biological context of NCL


Anatomical context of NCL

  • Nucleolin functions in ribosome biogenesis and contains an acidic N terminus that binds nuclear localization sequences [17].
  • Additionally, nucleolin levels were dramatically decreased in extracts containing the cytoplasm and plasma membrane [1].
  • Here, we report our findings that UV irradiation or camptothecin treatment of U937 cells induced apoptosis and caused a significant change in the levels and localization of nucleolin within the nucleus [1].
  • Both proteins were co-immunoprecipitated from HeLa cell nuclear extract by either monoclonal anti-C23 or monoclonal anti-B23 [18].
  • These results show that cell surface nucleolin is a specific marker of angiogenic endothelial cells within the vasculature [19].

Associations of NCL with chemical compounds

  • These alterations could be abrogated by pre-incubation with an inhibitor of PARP-1 (3-aminobenzamide), and our data support a potential role for nucleolin in removing cleaved PARP-1 from dying cells [1].
  • Antibodies and cell surface biotin labeling revealed nucleolin at the surface of actively growing cells, and these cells bound and internalized fluorescein-conjugated F3 peptide, transporting it into the nucleus [19].
  • This binding was inhibited by anti-nucleolin antibody, by polylactosamine-containing oligosaccharides, and by anti-CD43 antibody [20].
  • Nucleolin-transfected HEK293 cells expressed nucleolin on the cell surface and bound the early apoptotic cells but not phosphatidylserine-exposing late apoptotic cells [20].
  • Scanning clustered alanine substitution mutants library of NS5B revealed two sites on NS5B that binds nucleolin [3].

Physical interactions of NCL

  • Nucleolin interacts with telomerase [21].
  • We suggest a biological role of nucleolin in binding of GR in the nucleolus [22].
  • We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb, but not B-Myb DNA-binding domains [23].
  • The growth factor midkine (MK) has been reported to bind heparan sulfate and nucleolin, two components of the cell surface implicated in the attachment of HIV-1 particles [24].
  • The target cell substrates of granzymes are unknown, but granzyme A binding and cleavage of the nuclear shuttle protein nucleolin in target cells demonstrates that granzymes may act on nuclear substrates [25].

Enzymatic interactions of NCL

  • Furthermore, both nucleolin and cleaved PARP-1 were detected in the culture medium of cells undergoing apoptosis, associated with particles of a size consistent with apoptotic bodies [1].
  • Moreover, as the pattern of staining does not vary using casein kinase II- and cdc2-phosphorylated nucleolin or dephosphorylated nucleolin, we conclude that the reduction of the silver ions is not linked to the phosphorylation state of the molecule [26].

Co-localisations of NCL

  • Furthermore, nucleolin co-localized with p53 to these foci, suggesting that these foci were nucleolar structures [27].
  • RPS19 was detected primarily in the nucleus, and more specifically in the nucleoli, where RPS19 colocalized with the nucleolar protein nucleolin [28].

Regulatory relationships of NCL


Other interactions of NCL


Analytical, diagnostic and therapeutic context of NCL


  1. Apoptosis in leukemia cells is accompanied by alterations in the levels and localization of nucleolin. Mi, Y., Thomas, S.D., Xu, X., Casson, L.K., Miller, D.M., Bates, P.J. J. Biol. Chem. (2003) [Pubmed]
  2. The anti-HIV cytokine midkine binds the cell surface-expressed nucleolin as a low affinity receptor. Said, E.A., Krust, B., Nisole, S., Svab, J., Briand, J.P., Hovanessian, A.G. J. Biol. Chem. (2002) [Pubmed]
  3. Direct interaction between nucleolin and hepatitis C virus NS5B. Hirano, M., Kaneko, S., Yamashita, T., Luo, H., Qin, W., Shirota, Y., Nomura, T., Kobayashi, K., Murakami, S. J. Biol. Chem. (2003) [Pubmed]
  4. Pleiotrophin inhibits HIV infection by binding the cell surface-expressed nucleolin. Said, E.A., Courty, J., Svab, J., Delbé, J., Krust, B., Hovanessian, A.G. FEBS J. (2005) [Pubmed]
  5. Telomere length variation and maintenance in hepatocarcinogenesis. Yokota, T., Suda, T., Igarashi, M., Kuroiwa, T., Waguri, N., Kawai, H., Mita, Y., Aoyagi, Y. Cancer (2003) [Pubmed]
  6. Cdc2 phosphorylation of nucleolin demarcates mitotic stages and Alzheimer's disease pathology. Dranovsky, A., Vincent, I., Gregori, L., Schwarzman, A., Colflesh, D., Enghild, J., Strittmatter, W., Davies, P., Goldgaber, D. Neurobiol. Aging (2001) [Pubmed]
  7. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Gabellini, D., Green, M.R., Tupler, R. Cell (2002) [Pubmed]
  8. Nuclear export of proteins: the role of nuclear retention. Schmidt-Zachmann, M.S., Dargemont, C., Kühn, L.C., Nigg, E.A. Cell (1993) [Pubmed]
  9. Nucleolin and YB-1 are required for JNK-mediated interleukin-2 mRNA stabilization during T-cell activation. Chen, C.Y., Gherzi, R., Andersen, J.S., Gaietta, G., Jürchott, K., Royer, H.D., Mann, M., Karin, M. Genes Dev. (2000) [Pubmed]
  10. Nucleolin as activator of human papillomavirus type 18 oncogene transcription in cervical cancer. Grinstein, E., Wernet, P., Snijders, P.J., Rösl, F., Weinert, I., Jia, W., Kraft, R., Schewe, C., Schwabe, M., Hauptmann, S., Dietel, M., Meijer, C.J., Royer, H.D. J. Exp. Med. (2002) [Pubmed]
  11. Anchorage of HIV on permissive cells leads to coaggregation of viral particles with surface nucleolin at membrane raft microdomains. Nisole, S., Krust, B., Hovanessian, A.G. Exp. Cell Res. (2002) [Pubmed]
  12. Identification of V3 loop-binding proteins as potential receptors implicated in the binding of HIV particles to CD4(+) cells. Callebaut, C., Blanco, J., Benkirane, N., Krust, B., Jacotot, E., Guichard, G., Seddiki, N., Svab, J., Dam, E., Muller, S., Briand, J.P., Hovanessian, A.G. J. Biol. Chem. (1998) [Pubmed]
  13. Pharmacokinetics of a new human monoclonal antibody against cytomegalovirus. Third communication: correspondence of the idiotype activity and virus neutralization activity of the new monoclonal antibody, regavirumab in rat serum and its pharmacokinetics in rats and monkeys. Arizono, H., Sugano, T., Kaida, S., Shibusawa, K., Karasawa, Y., Esumi, Y., Kondo, S., Kiyoki, M. Arzneimittel-Forschung. (1994) [Pubmed]
  14. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells. Tate, A., Isotani, S., Bradley, M.J., Sikes, R.A., Davis, R., Chung, L.W., Edlund, M. BMC Cancer (2006) [Pubmed]
  15. Stress-dependent nucleolin mobilization mediated by p53-nucleolin complex formation. Daniely, Y., Dimitrova, D.D., Borowiec, J.A. Mol. Cell. Biol. (2002) [Pubmed]
  16. Nucleolar localization of aprataxin is dependent on interaction with nucleolin and on active ribosomal DNA transcription. Becherel, O.J., Gueven, N., Birrell, G.W., Schreiber, V., Suraweera, A., Jakob, B., Taucher-Scholz, G., Lavin, M.F. Hum. Mol. Genet. (2006) [Pubmed]
  17. Role for nucleolin/Nsr1 in the cellular localization of topoisomerase I. Edwards, T.K., Saleem, A., Shaman, J.A., Dennis, T., Gerigk, C., Oliveros, E., Gartenberg, M.R., Rubin, E.H. J. Biol. Chem. (2000) [Pubmed]
  18. C23 interacts with B23, a putative nucleolar-localization-signal-binding protein. Li, Y.P., Busch, R.K., Valdez, B.C., Busch, H. Eur. J. Biochem. (1996) [Pubmed]
  19. Nucleolin expressed at the cell surface is a marker of endothelial cells in angiogenic blood vessels. Christian, S., Pilch, J., Akerman, M.E., Porkka, K., Laakkonen, P., Ruoslahti, E. J. Cell Biol. (2003) [Pubmed]
  20. A multifunctional shuttling protein nucleolin is a macrophage receptor for apoptotic cells. Hirano, K., Miki, Y., Hirai, Y., Sato, R., Itoh, T., Hayashi, A., Yamanaka, M., Eda, S., Beppu, M. J. Biol. Chem. (2005) [Pubmed]
  21. Nucleolin interacts with telomerase. Khurts, S., Masutomi, K., Delgermaa, L., Arai, K., Oishi, N., Mizuno, H., Hayashi, N., Hahn, W.C., Murakami, S. J. Biol. Chem. (2004) [Pubmed]
  22. Identification of nucleolin as a glucocorticoid receptor interacting protein. Schulz, M., Schneider, S., Lottspeich, F., Renkawitz, R., Eggert, M. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  23. Nucleolin, a novel partner for the Myb transcription factor family that regulates their activity. Ying, G.G., Proost, P., van Damme, J., Bruschi, M., Introna, M., Golay, J. J. Biol. Chem. (2000) [Pubmed]
  24. Inhibition of HIV infection by the cytokine midkine. Callebaut, C., Nisole, S., Briand, J.P., Krust, B., Hovanessian, A.G. Virology (2001) [Pubmed]
  25. Hypothesis: cytotoxic lymphocyte granule serine proteases activate target cell endonucleases to trigger apoptosis. Smyth, M.J., Browne, K.A., Thia, K.Y., Apostolidis, V.A., Kershaw, M.H., Trapani, J.A. Clin. Exp. Pharmacol. Physiol. (1994) [Pubmed]
  26. Nucleolin is an Ag-NOR protein; this property is determined by its amino-terminal domain independently of its phosphorylation state. Roussel, P., Belenguer, P., Amalric, F., Hernandez-Verdun, D. Exp. Cell Res. (1992) [Pubmed]
  27. Accumulation of soluble and nucleolar-associated p53 proteins following cellular stress. Klibanov, S.A., O'Hagan, H.M., Ljungman, M. J. Cell. Sci. (2001) [Pubmed]
  28. Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan anemia patients: potential insights into pathophysiology. Da Costa, L., Tchernia, G., Gascard, P., Lo, A., Meerpohl, J., Niemeyer, C., Chasis, J.A., Fixler, J., Mohandas, N. Blood (2003) [Pubmed]
  29. Role of nucleolin in posttranscriptional control of MMP-9 expression. Fähling, M., Steege, A., Perlewitz, A., Nafz, B., Mrowka, R., Persson, P.B., Thiele, B.J. Biochim. Biophys. Acta (2005) [Pubmed]
  30. Activation of the EBV/C3d receptor (CR2, CD21) on human B lymphocyte surface triggers tyrosine phosphorylation of the 95-kDa nucleolin and its interaction with phosphatidylinositol 3 kinase. Barel, M., Le Romancer, M., Frade, R. J. Immunol. (2001) [Pubmed]
  31. Xylocydine, a novel inhibitor of cyclin-dependent kinases, prevents the tumor necrosis factor-related apoptosis-inducing ligand-induced apoptotic cell death of SK-HEP-1 cells. Ham, Y.M., Choi, K.J., Song, S.Y., Jin, Y.H., Chun, M.W., Lee, S.K. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  32. Nucleolin is a histone chaperone with FACT-like activity and assists remodeling of nucleosomes. Angelov, D., Bondarenko, V.A., Almagro, S., Menoni, H., Mongélard, F., Hans, F., Mietton, F., Studitsky, V.M., Hamiche, A., Dimitrov, S., Bouvet, P. EMBO J. (2006) [Pubmed]
  33. Cellular adhesion mediated by factor J, a complement inhibitor. Evidence for nucleolin involvement. Larrucea, S., González-Rubio, C., Cambronero, R., Ballou, B., Bonay, P., López-Granados, E., Bouvet, P., Fontán, G., Fresno, M., López-Trascasa, M. J. Biol. Chem. (1998) [Pubmed]
  34. Identification of a nucleolin binding site in human topoisomerase I. Bharti, A.K., Olson, M.O., Kufe, D.W., Rubin, E.H. J. Biol. Chem. (1996) [Pubmed]
  35. Nucleolin undergoes partial N- and O-glycosylations in the extranuclear cell compartment. Carpentier, M., Morelle, W., Coddeville, B., Pons, A., Masson, M., Mazurier, J., Legrand, D. Biochemistry (2005) [Pubmed]
  36. Prognostic value of p53 expression in Wilms' tumor in children. Skotnicka-Klonowicz, G., Kobos, J., Łoś, E., Trejster, E., Szymik-Kontorowicz, S., Daszkiewicz, P. Med. Sci. Monit. (2001) [Pubmed]
  37. Nucleolin is a protein kinase C-zeta substrate. Connection between cell surface signaling and nucleus in PC12 cells. Zhou, G., Seibenhener, M.L., Wooten, M.W. J. Biol. Chem. (1997) [Pubmed]
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