Nucleolin Explained

Nucleolin is a protein that in humans is encoded by the NCL gene.^{[1] [2]}

Gene

The human NCL gene is located on chromosome 2 and consists of 14 exons with 13 introns and spans approximately 11kb. Intron 11 of the NCL gene encodes a small nucleolar RNA, termed U20.^[3]

Function

Nucleolin is the major nucleolar protein of growing eukaryotic cells. It is found associated with intranucleolar chromatin and pre-ribosomal particles. It induces chromatin decondensation by binding to histone H1. It is thought to play a role in pre-rRNA transcription and ribosome assembly. May play a role in the process of transcriptional elongation. Binds RNA oligonucleotides with 5'-UUAGGG-3' repeats more tightly than the telomeric single-stranded DNA 5'-TTAGGG-3' repeats.

Nucleolin is also able to act as a transcriptional coactivator with Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII).^[4]

Clinical significance

Midkine and pleiotrophin bind to cell-surface nucleolin as a low affinity receptor. This binding can inhibit HIV infection.^{[5] [6]}

Nucleolin at the cell surface is the receptor for the respiratory syncytial virus (RSV) fusion protein.^[7] Interference with the nucleolinRSV fusion protein interaction has been shown to be therapeutic against RSV infection in cell cultures and animal models.^{[8] [9] [10] [11]}

Interactions

Nucleolin has been shown to interact with:

• MTDH,^[12]
• CSNK2A2,^[13]
• Centaurin, alpha 1,^[14]
• HuR,^[15]
• NPM1,^[16]
• P53,^[17]
• PPP1CB,^[18]
• S100A11,^[19]
• Sjögren syndrome antigen B,^[20]
• TOP1,^{[21] [22]} and
• Telomerase reverse transcriptase.^[23]

Further reading

• Tuteja R, Tuteja N . Nucleolin: a multifunctional major nucleolar phosphoprotein . Critical Reviews in Biochemistry and Molecular Biology . 33 . 6 . 407–36 . 1999 . 9918513 . 10.1080/10409239891204260 .
• Pasternack MS, Bleier KJ, McInerney TN . Granzyme A binding to target cell proteins. Granzyme A binds to and cleaves nucleolin in vitro . The Journal of Biological Chemistry . 266 . 22 . 14703–8 . Aug 1991 . 10.1016/S0021-9258(18)98743-0 . 1860869 . free .
• Belenguer P, Caizergues-Ferrer M, Labbé JC, Dorée M, Amalric F . Mitosis-specific phosphorylation of nucleolin by p34cdc2 protein kinase . Molecular and Cellular Biology . 10 . 7 . 3607–18 . Jul 1990 . 2192260 . 360797 . 10.1128/MCB.10.7.3607.
• Srivastava M, Fleming PJ, Pollard HB, Burns AL . Cloning and sequencing of the human nucleolin cDNA . FEBS Letters . 250 . 1 . 99–105 . Jun 1989 . 2737305 . 10.1016/0014-5793(89)80692-1 . 8690886 . free .
• Tuteja N, Huang NW, Skopac D, Tuteja R, Hrvatic S, Zhang J, Pongor S, Joseph G, Faucher C, Amalric F . Human DNA helicase IV is nucleolin, an RNA helicase modulated by phosphorylation . Gene . 160 . 2 . 143–8 . Jul 1995 . 7642087 . 10.1016/0378-1119(95)00207-M .
• Jordan P, Heid H, Kinzel V, Kübler D . Major cell surface-located protein substrates of an ecto-protein kinase are homologs of known nuclear proteins . Biochemistry . 33 . 49 . 14696–706 . Dec 1994 . 7993898 . 10.1021/bi00253a007 .
• Nicoloso M, Caizergues-Ferrer M, Michot B, Azum MC, Bachellerie JP . U20, a novel small nucleolar RNA, is encoded in an intron of the nucleolin gene in mammals . Molecular and Cellular Biology . 14 . 9 . 5766–76 . Sep 1994 . 8065311 . 359102 . 10.1128/mcb.14.9.5766 .
• Ishikawa F, Matunis MJ, Dreyfuss G, Cech TR . Nuclear proteins that bind the pre-mRNA 3' splice site sequence r(UUAG/G) and the human telomeric DNA sequence d(TTAGGG)n . Molecular and Cellular Biology . 13 . 7 . 4301–10 . Jul 1993 . 8321232 . 359985 . 10.1128/MCB.13.7.4301.
• Eggert M, Möws CC, Tripier D, Arnold R, Michel J, Nickel J, Schmidt S, Beato M, Renkawitz R . A fraction enriched in a novel glucocorticoid receptor-interacting protein stimulates receptor-dependent transcription in vitro . The Journal of Biological Chemistry . 270 . 51 . 30755–9 . Dec 1995 . 8530516 . 10.1074/jbc.270.51.30755 . 25642912 . free .
• Bharti AK, Olson MO, Kufe DW, Rubin EH . Identification of a nucleolin binding site in human topoisomerase I . The Journal of Biological Chemistry . 271 . 4 . 1993–7 . Jan 1996 . 8567649 . 10.1074/jbc.271.4.1993 . 25059254 . free .
• Li YP, Busch RK, Valdez BC, Busch H . C23 interacts with B23, a putative nucleolar-localization-signal-binding protein . European Journal of Biochemistry . 237 . 1 . 153–8 . Apr 1996 . 8620867 . 10.1111/j.1432-1033.1996.0153n.x . free .
• Li D, Dobrowolska G, Krebs EG . The physical association of casein kinase 2 with nucleolin . The Journal of Biological Chemistry . 271 . 26 . 15662–8 . Jun 1996 . 8663258 . 10.1074/jbc.271.26.15662 . 10750338 . free .
• Zhou G, Seibenhener ML, Wooten MW . Nucleolin is a protein kinase C-zeta substrate. Connection between cell surface signaling and nucleus in PC12 cells . The Journal of Biological Chemistry . 272 . 49 . 31130–7 . Dec 1997 . 9388266 . 10.1074/jbc.272.49.31130 . free .
• Haluska P, Saleem A, Edwards TK, Rubin EH . Interaction between the N-terminus of human topoisomerase I and SV40 large T antigen . Nucleic Acids Research . 26 . 7 . 1841–7 . Apr 1998 . 9512561 . 147454 . 10.1093/nar/26.7.1841 .
• Borggrefe T, Wabl M, Akhmedov AT, Jessberger R . A B-cell-specific DNA recombination complex . The Journal of Biological Chemistry . 273 . 27 . 17025–35 . Jul 1998 . 9642267 . 10.1074/jbc.273.27.17025 . 24347735 . free .
• Larrucea S, González-Rubio C, Cambronero R, Ballou B, Bonay P, López-Granados E, Bouvet P, Fontán G, Fresno M, López-Trascasa M . Cellular adhesion mediated by factor J, a complement inhibitor. Evidence for nucleolin involvement . The Journal of Biological Chemistry . 273 . 48 . 31718–25 . Nov 1998 . 9822633 . 10.1074/jbc.273.48.31718 . 8004314 . free .
• Parada CA, Roeder RG . A novel RNA polymerase II-containing complex potentiates Tat-enhanced HIV-1 transcription . The EMBO Journal . 18 . 13 . 3688–701 . Jul 1999 . 10393184 . 1171446 . 10.1093/emboj/18.13.3688 .

Notes and References

1. Srivastava M, McBride OW, Fleming PJ, Pollard HB, Burns AL . Genomic organization and chromosomal localization of the human nucleolin gene . The Journal of Biological Chemistry . 265 . 25 . 14922–31 . Sep 1990 . 10.1016/S0021-9258(18)77205-0 . 2394707 . free .
2. Erard MS, Belenguer P, Caizergues-Ferrer M, Pantaloni A, Amalric F . A major nucleolar protein, nucleolin, induces chromatin decondensation by binding to histone H1 . European Journal of Biochemistry . 175 . 3 . 525–30 . Aug 1988 . 3409881 . 10.1111/j.1432-1033.1988.tb14224.x . free .
3. Web site: Entrez Gene: NCL nucleolin.
4. Litchfield LM, Riggs KA, Hockenberry AM, Oliver LD, Barnhart KG, Cai J, Pierce WM, Ivanova MM, Bates PJ, Appana SN, Datta S, Kulesza P, McBryan J, Young LS, Klinge CM . Identification and characterization of nucleolin as a COUP-TFII coactivator of retinoic acid receptor β transcription in breast cancer cells . PLOS ONE . 7 . 5 . May 2012 . 3365040 . 10.1371/journal.pone.0038278 . 22693611 . e38278. 2012PLoSO...738278L . free .
5. Said EA, Krust B, Nisole S, Svab J, Briand JP, Hovanessian AG . The anti-HIV cytokine midkine binds the cell surface-expressed nucleolin as a low affinity receptor . The Journal of Biological Chemistry . 277 . 40 . 37492–502 . Oct 2002 . 12147681 . 10.1074/jbc.M201194200 . 41621217 . free .
6. Said EA, Courty J, Svab J, Delbé J, Krust B, Hovanessian AG . Pleiotrophin inhibits HIV infection by binding the cell surface-expressed nucleolin . The FEBS Journal . 272 . 18 . 4646–59 . Sep 2005 . 16156786 . 10.1111/j.1742-4658.2005.04870.x . 21153881 . free .
7. Tayyari F, Marchant D, Moraes TJ, Duan W, Mastrangelo P, Hegele RG . Identification of nucleolin as a cellular receptor for human respiratory syncytial virus . Nature Medicine . 17 . 9 . 1132–5 . Sep 2011 . 21841784 . 10.1038/nm.2444 . 205388029 .
8. Bilawchuk LM, Griffiths CD, Jensen LD, Elawar F, Marchant DJ . The Susceptibilities of Respiratory Syncytial Virus to Nucleolin Receptor Blocking and Antibody Neutralization are Dependent upon the Method of Virus Purification . Viruses . 9 . 8 . 207 . Aug 2017 . 28771197 . 10.3390/v9080207 . 5580464 . free .
9. Mastrangelo P, Hegele RG . The RSV fusion receptor: not what everyone expected it to be . Microbes and Infection / Institut Pasteur . 14 . 13 . 1205–10 . Nov 2012 . 22884716 . 10.1016/j.micinf.2012.07.015 .
10. Mastrangelo P, Hegele RG . RSV fusion: time for a new model . Viruses . 5 . 3 . 873–85 . Mar 2013 . 23518574 . 10.3390/v5030873 . 3705301. free .
11. Shakeri A, Mastrangelo P, Griffin JK, Moraes TJ, Hegele RG . Respiratory syncytial virus receptor expression in the mouse and viral tropism . Histology and Histopathology . 30. 30. Nov 2014 . 25374027 . 10.14670/HH-30.401. 401–411.
12. Lee, Seong-Jae, et al. . Identification of Nucleolin as a Novel AEG-1-Interacting Protein in Breast Cancer via Interactome Profiling. . Cancers . 13 . 11 . 2842 . Jun 2021 . 34200450 . 10.3390/cancers13112842 . 8201222 . 235436955 . free .
13. Li D, Dobrowolska G, Krebs EG . The physical association of casein kinase 2 with nucleolin . The Journal of Biological Chemistry . 271 . 26 . 15662–8 . Jun 1996 . 8663258 . 10.1074/jbc.271.26.15662 . 10750338 . free .
14. Dubois T, Zemlickova E, Howell S, Aitken A . Centaurin-alpha 1 associates in vitro and in vivo with nucleolin . Biochemical and Biophysical Research Communications . 301 . 2 . 502–8 . Feb 2003 . 12565890 . 10.1016/s0006-291x(02)03010-3.
15. Tominaga K, Srikantan S, Lee EK, Subaran SS, Martindale JL, Abdelmohsen K, Gorospe M . Competitive regulation of nucleolin expression by HuR and miR-494 . Molecular and Cellular Biology . 31 . 20 . 4219–31 . Oct 2011 . 21859890 . 3187287 . 10.1128/MCB.05955-11 .
16. Li YP, Busch RK, Valdez BC, Busch H . C23 interacts with B23, a putative nucleolar-localization-signal-binding protein . European Journal of Biochemistry . 237 . 1 . 153–8 . Apr 1996 . 8620867 . 10.1111/j.1432-1033.1996.0153n.x . free .
17. Daniely Y, Dimitrova DD, Borowiec JA . Stress-dependent nucleolin mobilization mediated by p53-nucleolin complex formation . Molecular and Cellular Biology . 22 . 16 . 6014–22 . Aug 2002 . 12138209 . 133981 . 10.1128/mcb.22.16.6014-6022.2002 .
18. Morimoto H, Okamura H, Haneji T . Interaction of protein phosphatase 1 delta with nucleolin in human osteoblastic cells . The Journal of Histochemistry and Cytochemistry . 50 . 9 . 1187–93 . Sep 2002 . 12185196 . 10.1177/002215540205000905 . 24950287 . free .
19. Sakaguchi M, Miyazaki M, Takaishi M, Sakaguchi Y, Makino E, Kataoka N, Yamada H, Namba M, Huh NH . S100C/A11 is a key mediator of Ca(2+)-induced growth inhibition of human epidermal keratinocytes . The Journal of Cell Biology . 163 . 4 . 825–35 . Nov 2003 . 14623863 . 2173690 . 10.1083/jcb.200304017 .
20. Fouraux MA, Bouvet P, Verkaart S, van Venrooij WJ, Pruijn GJ . Nucleolin associates with a subset of the human Ro ribonucleoprotein complexes . Journal of Molecular Biology . 320 . 3 . 475–88 . Jul 2002 . 12096904 . 10.1016/s0022-2836(02)00518-1 . 2066/121576 . free .
21. Haluska P, Saleem A, Edwards TK, Rubin EH . Interaction between the N-terminus of human topoisomerase I and SV40 large T antigen . Nucleic Acids Research . 26 . 7 . 1841–7 . Apr 1998 . 9512561 . 147454 . 10.1093/nar/26.7.1841 .
22. Bharti AK, Olson MO, Kufe DW, Rubin EH . Identification of a nucleolin binding site in human topoisomerase I . The Journal of Biological Chemistry . 271 . 4 . 1993–7 . Jan 1996 . 8567649 . 10.1074/jbc.271.4.1993 . 25059254 . free .
23. Khurts S, Masutomi K, Delgermaa L, Arai K, Oishi N, Mizuno H, Hayashi N, Hahn WC, Murakami S . Nucleolin interacts with telomerase . The Journal of Biological Chemistry . 279 . 49 . 51508–15 . Dec 2004 . 15371412 . 10.1074/jbc.M407643200 . 41394148 . free . 2297/15897 . free .