Nucleolin

Nucleolin is a protein that in humans is encoded by the NCL gene.^[5][6]

NCL
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2FC8, 2FC9, 2KRR
Identifiers
Aliases	NCL, C23, nucleolin, Nsr1
External IDs	OMIM: 164035; MGI: 97286; HomoloGene: 136488; GeneCards: NCL; OMA:NCL - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q37.1 Start 231,453,531 bp[1] End 231,483,641 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 C5|1 43.94 cM Start 86,272,441 bp[2] End 86,287,122 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ventricular zone ganglionic eminence appendix body of pancreas smooth muscle tissue Achilles tendon left ovary right ovary epithelium of colon sural nerve Top expressed in tail of embryo yolk sac epiblast genital tubercle neural layer of retina primary oocyte secondary oocyte zygote ventricular zone placenta More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding telomeric DNA binding protein C-terminus binding protein binding RNA binding identical protein binding nucleic acid binding DNA topoisomerase binding mRNA 5'-UTR binding Cellular component cytoplasm membrane nucleoplasm cell cortex nucleolus cytoplasmic ribonucleoprotein granule extracellular exosome nucleus ribonucleoprotein complex Biological process positive regulation of transcription of nucleolar large rRNA by RNA polymerase I angiogenesis positive regulation of transcription by RNA polymerase II cellular response to epidermal growth factor stimulus negative regulation of translation cellular response to leukemia inhibitory factor Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4691 17975 Ensembl ENSG00000115053 ENSMUSG00000026234 UniProt P19338 P09405 RefSeq (mRNA) NM_005381 NM_010880 RefSeq (protein) NP_005372 NP_035010 Location (UCSC) Chr 2: 231.45 – 231.48 Mb Chr 1: 86.27 – 86.29 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[7]

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).^[8]

Clinical significance

Midkine and pleiotrophin bind to cell-surface nucleolin as a low affinity receptor. This binding can inhibit HIV infection.^[9][10]

Nucleolin at the cell surface is the receptor for the respiratory syncytial virus (RSV) fusion protein.^[11] Interference with the nucleolin–RSV fusion protein interaction has been shown to be therapeutic against RSV infection in cell cultures and animal models.^{[12][13][14][15]}

Interactions

Nucleolin has been shown to interact with:

• MTDH,^[16]
• CSNK2A2,^[17]
• Centaurin, alpha 1,^[18]
• HuR,^[19]
• NPM1,^[20]
• P53,^[21]
• PPP1CB,^[22]
• S100A11,^[23]
• Sjögren syndrome antigen B,^[24]
• TOP1,^[25][26] and
• Telomerase reverse transcriptase.^[27]

References

1. GRCh38: Ensembl release 89: ENSG00000115053 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026234 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Srivastava M, McBride OW, Fleming PJ, Pollard HB, Burns AL (Sep 1990). "Genomic organization and chromosomal localization of the human nucleolin gene". The Journal of Biological Chemistry. 265 (25): 14922–31. doi:10.1016/S0021-9258(18)77205-0. PMID 2394707.
6. Erard MS, Belenguer P, Caizergues-Ferrer M, Pantaloni A, Amalric F (Aug 1988). "A major nucleolar protein, nucleolin, induces chromatin decondensation by binding to histone H1". European Journal of Biochemistry. 175 (3): 525–30. doi:10.1111/j.1432-1033.1988.tb14224.x. PMID 3409881.
7. "Entrez Gene: NCL nucleolin".
8. 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 (May 2012). "Identification and characterization of nucleolin as a COUP-TFII coactivator of retinoic acid receptor β transcription in breast cancer cells". PLOS ONE. 7 (5): e38278. Bibcode:2012PLoSO...738278L. doi:10.1371/journal.pone.0038278. PMC 3365040. PMID 22693611.
9. Said EA, Krust B, Nisole S, Svab J, Briand JP, Hovanessian AG (Oct 2002). "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. doi:10.1074/jbc.M201194200. PMID 12147681. S2CID 41621217.
10. Said EA, Courty J, Svab J, Delbé J, Krust B, Hovanessian AG (Sep 2005). "Pleiotrophin inhibits HIV infection by binding the cell surface-expressed nucleolin". The FEBS Journal. 272 (18): 4646–59. doi:10.1111/j.1742-4658.2005.04870.x. PMID 16156786. S2CID 21153881.
11. Tayyari F, Marchant D, Moraes TJ, Duan W, Mastrangelo P, Hegele RG (Sep 2011). "Identification of nucleolin as a cellular receptor for human respiratory syncytial virus". Nature Medicine. 17 (9): 1132–5. doi:10.1038/nm.2444. PMID 21841784. S2CID 205388029.
12. Bilawchuk LM, Griffiths CD, Jensen LD, Elawar F, Marchant DJ (Aug 2017). "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. doi:10.3390/v9080207. PMC 5580464. PMID 28771197.
13. Mastrangelo P, Hegele RG (Nov 2012). "The RSV fusion receptor: not what everyone expected it to be". Microbes and Infection / Institut Pasteur. 14 (13): 1205–10. doi:10.1016/j.micinf.2012.07.015. PMID 22884716.
14. Mastrangelo P, Hegele RG (Mar 2013). "RSV fusion: time for a new model". Viruses. 5 (3): 873–85. doi:10.3390/v5030873. PMC 3705301. PMID 23518574.
15. Shakeri A, Mastrangelo P, Griffin JK, Moraes TJ, Hegele RG (Nov 2014). "Respiratory syncytial virus receptor expression in the mouse and viral tropism". Histology and Histopathology. 30 (30): 401–411. doi:10.14670/HH-30.401. PMID 25374027.
16. Lee, Seong-Jae, et al. (Jun 2021). "Identification of Nucleolin as a Novel AEG-1-Interacting Protein in Breast Cancer via Interactome Profiling". Cancers. 13 (11): 2842. doi:10.3390/cancers13112842. PMC 8201222. PMID 34200450. S2CID 235436955.
17. Li D, Dobrowolska G, Krebs EG (Jun 1996). "The physical association of casein kinase 2 with nucleolin". The Journal of Biological Chemistry. 271 (26): 15662–8. doi:10.1074/jbc.271.26.15662. PMID 8663258. S2CID 10750338.
18. Dubois T, Zemlickova E, Howell S, Aitken A (Feb 2003). "Centaurin-alpha 1 associates in vitro and in vivo with nucleolin". Biochemical and Biophysical Research Communications. 301 (2): 502–8. doi:10.1016/s0006-291x(02)03010-3. PMID 12565890.
19. Tominaga K, Srikantan S, Lee EK, Subaran SS, Martindale JL, Abdelmohsen K, Gorospe M (Oct 2011). "Competitive regulation of nucleolin expression by HuR and miR-494". Molecular and Cellular Biology. 31 (20): 4219–31. doi:10.1128/MCB.05955-11. PMC 3187287. PMID 21859890.
20. Li YP, Busch RK, Valdez BC, Busch H (Apr 1996). "C23 interacts with B23, a putative nucleolar-localization-signal-binding protein". European Journal of Biochemistry. 237 (1): 153–8. doi:10.1111/j.1432-1033.1996.0153n.x. PMID 8620867.
21. Daniely Y, Dimitrova DD, Borowiec JA (Aug 2002). "Stress-dependent nucleolin mobilization mediated by p53-nucleolin complex formation". Molecular and Cellular Biology. 22 (16): 6014–22. doi:10.1128/mcb.22.16.6014-6022.2002. PMC 133981. PMID 12138209.
22. Morimoto H, Okamura H, Haneji T (Sep 2002). "Interaction of protein phosphatase 1 delta with nucleolin in human osteoblastic cells". The Journal of Histochemistry and Cytochemistry. 50 (9): 1187–93. doi:10.1177/002215540205000905. PMID 12185196. S2CID 24950287.
23. Sakaguchi M, Miyazaki M, Takaishi M, Sakaguchi Y, Makino E, Kataoka N, Yamada H, Namba M, Huh NH (Nov 2003). "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. doi:10.1083/jcb.200304017. PMC 2173690. PMID 14623863.
24. Fouraux MA, Bouvet P, Verkaart S, van Venrooij WJ, Pruijn GJ (Jul 2002). "Nucleolin associates with a subset of the human Ro ribonucleoprotein complexes". Journal of Molecular Biology. 320 (3): 475–88. doi:10.1016/s0022-2836(02)00518-1. hdl:2066/121576. PMID 12096904.
25. Haluska P, Saleem A, Edwards TK, Rubin EH (Apr 1998). "Interaction between the N-terminus of human topoisomerase I and SV40 large T antigen". Nucleic Acids Research. 26 (7): 1841–7. doi:10.1093/nar/26.7.1841. PMC 147454. PMID 9512561.
26. Bharti AK, Olson MO, Kufe DW, Rubin EH (Jan 1996). "Identification of a nucleolin binding site in human topoisomerase I". The Journal of Biological Chemistry. 271 (4): 1993–7. doi:10.1074/jbc.271.4.1993. PMID 8567649. S2CID 25059254.
27. Khurts S, Masutomi K, Delgermaa L, Arai K, Oishi N, Mizuno H, Hayashi N, Hahn WC, Murakami S (Dec 2004). "Nucleolin interacts with telomerase". The Journal of Biological Chemistry. 279 (49): 51508–15. doi:10.1074/jbc.M407643200. hdl:2297/15897. PMID 15371412. S2CID 41394148.

Further reading

• Tuteja R, Tuteja N (1999). "Nucleolin: a multifunctional major nucleolar phosphoprotein". Critical Reviews in Biochemistry and Molecular Biology. 33 (6): 407–36. doi:10.1080/10409239891204260. PMID 9918513.
• Pasternack MS, Bleier KJ, McInerney TN (Aug 1991). "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. doi:10.1016/S0021-9258(18)98743-0. PMID 1860869.
• Belenguer P, Caizergues-Ferrer M, Labbé JC, Dorée M, Amalric F (Jul 1990). "Mitosis-specific phosphorylation of nucleolin by p34cdc2 protein kinase". Molecular and Cellular Biology. 10 (7): 3607–18. doi:10.1128/MCB.10.7.3607. PMC 360797. PMID 2192260.
• Srivastava M, Fleming PJ, Pollard HB, Burns AL (Jun 1989). "Cloning and sequencing of the human nucleolin cDNA". FEBS Letters. 250 (1): 99–105. doi:10.1016/0014-5793(89)80692-1. PMID 2737305. S2CID 8690886.
• Tuteja N, Huang NW, Skopac D, Tuteja R, Hrvatic S, Zhang J, Pongor S, Joseph G, Faucher C, Amalric F (Jul 1995). "Human DNA helicase IV is nucleolin, an RNA helicase modulated by phosphorylation". Gene. 160 (2): 143–8. doi:10.1016/0378-1119(95)00207-M. PMID 7642087.
• Jordan P, Heid H, Kinzel V, Kübler D (Dec 1994). "Major cell surface-located protein substrates of an ecto-protein kinase are homologs of known nuclear proteins". Biochemistry. 33 (49): 14696–706. doi:10.1021/bi00253a007. PMID 7993898.
• Nicoloso M, Caizergues-Ferrer M, Michot B, Azum MC, Bachellerie JP (Sep 1994). "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. doi:10.1128/mcb.14.9.5766. PMC 359102. PMID 8065311.
• Ishikawa F, Matunis MJ, Dreyfuss G, Cech TR (Jul 1993). "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. doi:10.1128/MCB.13.7.4301. PMC 359985. PMID 8321232.
• Eggert M, Möws CC, Tripier D, Arnold R, Michel J, Nickel J, Schmidt S, Beato M, Renkawitz R (Dec 1995). "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. doi:10.1074/jbc.270.51.30755. PMID 8530516. S2CID 25642912.
• Bharti AK, Olson MO, Kufe DW, Rubin EH (Jan 1996). "Identification of a nucleolin binding site in human topoisomerase I". The Journal of Biological Chemistry. 271 (4): 1993–7. doi:10.1074/jbc.271.4.1993. PMID 8567649. S2CID 25059254.
• Li YP, Busch RK, Valdez BC, Busch H (Apr 1996). "C23 interacts with B23, a putative nucleolar-localization-signal-binding protein". European Journal of Biochemistry. 237 (1): 153–8. doi:10.1111/j.1432-1033.1996.0153n.x. PMID 8620867.
• Li D, Dobrowolska G, Krebs EG (Jun 1996). "The physical association of casein kinase 2 with nucleolin". The Journal of Biological Chemistry. 271 (26): 15662–8. doi:10.1074/jbc.271.26.15662. PMID 8663258. S2CID 10750338.
• Zhou G, Seibenhener ML, Wooten MW (Dec 1997). "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. doi:10.1074/jbc.272.49.31130. PMID 9388266.
• Haluska P, Saleem A, Edwards TK, Rubin EH (Apr 1998). "Interaction between the N-terminus of human topoisomerase I and SV40 large T antigen". Nucleic Acids Research. 26 (7): 1841–7. doi:10.1093/nar/26.7.1841. PMC 147454. PMID 9512561.
• Borggrefe T, Wabl M, Akhmedov AT, Jessberger R (Jul 1998). "A B-cell-specific DNA recombination complex". The Journal of Biological Chemistry. 273 (27): 17025–35. doi:10.1074/jbc.273.27.17025. PMID 9642267. S2CID 24347735.
• Larrucea S, González-Rubio C, Cambronero R, Ballou B, Bonay P, López-Granados E, Bouvet P, Fontán G, Fresno M, López-Trascasa M (Nov 1998). "Cellular adhesion mediated by factor J, a complement inhibitor. Evidence for nucleolin involvement". The Journal of Biological Chemistry. 273 (48): 31718–25. doi:10.1074/jbc.273.48.31718. PMID 9822633. S2CID 8004314.
• Parada CA, Roeder RG (Jul 1999). "A novel RNA polymerase II-containing complex potentiates Tat-enhanced HIV-1 transcription". The EMBO Journal. 18 (13): 3688–701. doi:10.1093/emboj/18.13.3688. PMC 1171446. PMID 10393184.