NPM1

NPM1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2LLH, 2P1B, 2VXD
Identifiers
Aliases	NPM1, B23, NPM, nucleophosmin (nucleolar phosphoprotein B23, numatrin)
External IDs	MGI: 106184 HomoloGene: 81697 GeneCards: NPM1
Gene ontology Molecular function • ribosomal large subunit binding • protein homodimerization activity • ribosomal small subunit binding • unfolded protein binding • transcription coactivator activity • protein kinase inhibitor activity • histone binding • Tat protein binding • NF-kappaB binding • protein binding • RNA binding • protein heterodimerization activity • nucleic acid binding • poly(A) RNA binding • protein kinase binding • phosphatidylinositol-3,4,5-trisphosphate binding • DNA binding • enzyme binding Cellular component • cytoplasm • cytosol • centrosome • membrane • focal adhesion • spindle pole centrosome • intracellular ribonucleoprotein complex • nucleoplasm • microtubule organizing center • nucleolus • cytoskeleton • nucleus Biological process • protein localization • centrosome cycle • regulation of eIF2 alpha phosphorylation by dsRNA • positive regulation of cell cycle G2/M phase transition • negative regulation of centrosome duplication • regulation of centriole replication • response to stress • negative regulation of apoptotic process • positive regulation of translation • CENP-A containing nucleosome assembly • positive regulation of transcription, DNA-templated • cell aging • positive regulation of NF-kappaB transcription factor activity • protein oligomerization • nucleocytoplasmic transport • positive regulation of cell proliferation • negative regulation of protein kinase activity by regulation of protein phosphorylation • regulation of endodeoxyribonuclease activity • regulation of endoribonuclease activity • ribosome assembly • intracellular protein transport • DNA repair • signal transduction • negative regulation of cell proliferation • positive regulation of DNA metabolic process • positive regulation of DNA replication • nucleosome assembly • positive regulation of catalytic activity • viral process • protein homooligomerization • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest • regulation of neuron apoptotic process Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4869	18148
Ensembl	ENSG00000181163	ENSMUSG00000057113
UniProt	P06748	Q61937
RefSeq (mRNA)	NM_001037738 NM_002520 NM_199185	NM_001252260 NM_001252261 NM_008722
RefSeq (protein)	NP_001032827.1 NP_002511.1 NP_954654.1	NP_032748.1
Location (UCSC)	Chr 5: 171.39 – 171.41 Mb	Chr 11: 33.15 – 33.16 Mb
PubMed search	[1]	[2]
Wikidata

View/Edit Human

View/Edit Mouse

Nucleophosmin (NPM), also known as nucleolar phosphoprotein B23 or numatrin, is a protein that in humans is encoded by the NPM1 gene.^[3][4]

Function

NPM1 is associated with nucleolar ribonucleoprotein structures and bind single-stranded and double-stranded nucleic acids, but it binds preferentially G-Quadruplex forming nucleic acids. It is involved in the biogenesis of ribosomes and may assist small basic proteins in their transport to the nucleolus. Its regulation through SUMOylation (by SENP3 and SENP5) is another facet of the proteins's regulation and cellular functions.

It is located in the nucleolus, but it can be translocated to the nucleoplasm in case of serum starvation or treatment with anticancer drugs. The protein is phosphorylated.

Nucleophosmin has multiple functions:^[5]

1. Histone chaperons
2. Ribosome biogenesis and transport
3. Genomic stability and DNA repair
4. Endoribonuclease activity
5. Centrosome duplication during cell cycle
6. Regulation of ARF-p53 tumor suppressor pathway
7. RNA helix destabilizing activity
8. Inhibition of caspase-activated DNase
9. Prevents apoptosis when located in nucleolus

Clinical significance

NPM1 gene is up-regulated, mutated and chromosomally translocated in many tumor types. Chromosomal aberrations involving NPM1 were found in patients with non-Hodgkin lymphoma, acute promyelocytic leukemia, myelodysplastic syndrome, and acute myelogenous leukemia.^[6] Heterozygous mice for NPM1 are vulnerable to tumor development. In solid tumors NPM1 is frequently found overexpressed, and it is thought that NPM1 could promote tumor growth by inactivation of the tumor suppressor p53/ARF pathway; on the contrary, when expressed at low levels, NPM1 could suppress tumor growth by the inhibition of centrosome duplication.

Of high importance is NPM involvement in acute myelogenous leukemia,^[7]

where a mutated protein lacking a folded C-terminal domain (NPM1c+) has been found in the cytoplasm in patients This aberrant localization has been linked to the development of the disease. Strategies against this subtype of acute myelogenous leukemia include the refolding of the C-terminal domain using pharmalogical chaperones and the displacement of the protein from nucleolus to nucleoplasm, which has been linked to apoptotic mechanisms.

Interactions

NPM1 has been shown to interact with

• AKT1,^[8]
• BARD1,^[9]
• BRCA1,^[9] and
• nucleolin.^[10]

Nucleophosmin has multiple binding partners:^[5]

1. rRNA
2. HIV Rev and Rex peptide
3. p53 tumor suppressor
4. ARF tumor suppressor
5. MDM2 (mouse double minute 2, ubiquitin ligase)
6. Ribosome protein S9
7. Phosphatidylinositol 3,4,5-triphosphate (PIP3)
8. Exportin-1 (CRM1, chromosome region maintenance)
9. Nucleolin/C23
10. Transcription target of myc oncogene

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. Liu QR, Chan PK (March 1993). "Characterization of seven processed pseudogenes of nucleophosmin/B23 in the human genome". DNA Cell Biol. 12 (2): 149–56. doi:10.1089/dna.1993.12.149. PMID 8471164.
4. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT (March 1994). "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Science. 263 (5151): 1281–4. doi:10.1126/science.8122112. PMID 8122112.
5. Lindström MS (2011). "NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling". Biochem Res Int. 2011: 195209. doi:10.1155/2011/195209. PMC 2989734. PMID 21152184.
6. Falini B, Nicoletti I, Bolli N, Martelli MP, Liso A, Gorello P, Mandelli F, Mecucci C, Martelli MF (April 2007). "Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias". Haematologica. 92 (4): 519–32. doi:10.3324/haematol.11007. PMID 17488663.
7. Meani, Natalia; Alcalay, Myriam (2014). "Role of nucleophosmin in acute myeloid leukemia". Expert Review of Anticancer Therapy. 9 (9): 1283–1294. doi:10.1586/era.09.84. ISSN 1473-7140.
8. Lee SB, Xuan Nguyen TL, Choi JW, Lee KH, Cho SW, Liu Z, Ye K, Bae SS, Ahn JY (October 2008). "Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival". Proc. Natl. Acad. Sci. U.S.A. 105 (43): 16584–9. doi:10.1073/pnas.0807668105. PMC 2569968. PMID 18931307.
9. Sato K, Hayami R, Wu W, Nishikawa T, Nishikawa H, Okuda Y, Ogata H, Fukuda M, Ohta T (July 2004). "Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase". J. Biol. Chem. 279 (30): 30919–22. doi:10.1074/jbc.C400169200. PMID 15184379.
10. Li YP, Busch RK, Valdez BC, Busch H (April 1996). "C23 interacts with B23, a putative nucleolar-localization-signal-binding protein". Eur. J. Biochem. 237 (1): 153–8. doi:10.1111/j.1432-1033.1996.0153n.x. PMID 8620867.

Further reading

• Yun C, Wang Y, Mukhopadhyay D, et al. (2008). "Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases". J Cell Biol. 183 (4): 589–95. doi:10.1083/jcb.200807185. PMC 2582899. PMID 19015314.
• Haindl M, Harasim T, Eick D, et al. (2008). "The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing". EMBO Reports. 9 (3): 273–279. doi:10.1038/embor.2008.3. PMC 2267381. PMID 18259216.
• Li L, Li HS, Pauza CD, et al. (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Res. 15 (11–12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571.
• Gjerset RA (2007). "DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer". J. Mol. Histol. 37 (5–7): 239–51. doi:10.1007/s10735-006-9040-y. PMID 16855788.
• Chen W, Rassidakis GZ, Medeiros LJ (2006). "Nucleophosmin gene mutations in acute myeloid leukemia". Arch. Pathol. Lab. Med. 130 (11): 1687–92. doi:10.1043/1543-2165(2006)130[1687:NGMIAM]2.0.CO;2. PMID 17076533.
• Falini B, Nicoletti I, Bolli N, et al. (2007). "Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias". Haematologica. 92 (4): 519–32. doi:10.3324/haematol.11007. PMID 17488663.
• Fankhauser C, Izaurralde E, Adachi Y, et al. (1991). "Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element". Mol. Cell. Biol. 11 (5): 2567–75. PMC 360026. PMID 2017166.
• Venkatesh LK, Mohammed S, Chinnadurai G (1990). "Functional domains of the HIV-1 rev gene required for trans-regulation and subcellular localization". Virology. 176 (1): 39–47. doi:10.1016/0042-6822(90)90228-J. PMID 2109912.
• Cochrane AW, Perkins A, Rosen CA (1990). "Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function". J. Virol. 64 (2): 881–5. PMC 249184. PMID 2404140.
• Chan PK, Chan WY, Yung BY, et al. (1986). "Amino acid sequence of a specific antigenic peptide of protein B23". J. Biol. Chem. 261 (30): 14335–41. PMID 2429957.
• Zhang XX, Thomis DC, Samuel CE (1989). "Isolation and characterization of a molecular cDNA clone of a human mRNA from interferon-treated cells encoding nucleolar protein B23, numatrin". Biochem. Biophys. Res. Commun. 164 (1): 176–84. doi:10.1016/0006-291X(89)91699-9. PMID 2478125.
• Hale TK, Mansfield BC (1990). "Nucleotide sequence of a cDNA clone representing a third allele of human protein B23". Nucleic Acids Res. 17 (23): 10112. PMC 335249. PMID 2602120.
• Chan WY, Liu QR, Borjigin J, et al. (1989). "Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth". Biochemistry. 28 (3): 1033–9. doi:10.1021/bi00429a017. PMID 2713355.
• Li XZ, McNeilage LJ, Whittingham S (1989). "The nucleotide sequence of a human cDNA encoding the highly conserved nucleolar phosphoprotein B23". Biochem. Biophys. Res. Commun. 163 (1): 72–8. doi:10.1016/0006-291X(89)92100-1. PMID 2775293.
• Chan PK, Aldrich M, Cook RG, Busch H (1986). "Amino acid sequence of protein B23 phosphorylation site". J. Biol. Chem. 261 (4): 1868–72. PMID 3944116.
• Bocker T, Bittinger A, Wieland W, et al. (1995). "In vitro and ex vivo expression of nucleolar proteins B23 and p120 in benign and malignant epithelial lesions of the prostate". Mod. Pathol. 8 (3): 226–31. PMID 7542384.
• Dundr M, Leno GH, Hammarskjöld ML, et al. (1995). "The roles of nucleolar structure and function in the subcellular location of the HIV-1 Rev protein". J. Cell. Sci. 108 (8): 2811–23. PMID 7593322.
• Miyazaki Y, Takamatsu T, Nosaka T, et al. (1995). "The cytotoxicity of human immunodeficiency virus type 1 Rev: implications for its interaction with the nucleolar protein B23". Exp. Cell Res. 219 (1): 93–101. doi:10.1006/excr.1995.1209. PMID 7628555.
• Szebeni A, Herrera JE, Olson MO (1995). "Interaction of nucleolar protein B23 with peptides related to nuclear localization signals". Biochemistry. 34 (25): 8037–42. doi:10.1021/bi00025a009. PMID 7794916.
• Kato S, Sekine S, Oh SW, et al. (1995). "Construction of a human full-length cDNA bank". Gene. 150 (2): 243–50. doi:10.1016/0378-1119(94)90433-2. PMID 7821789.
• Marasco WA, Szilvay AM, Kalland KH, et al. (1995). "Spatial association of HIV-1 tat protein and the nucleolar transport protein B23 in stably transfected Jurkat T-cells". Arch. Virol. 139 (1–2): 133–54. doi:10.1007/BF01309460. PMID 7826206.
• Valdez BC, Perlaky L, Henning D, et al. (1994). "Identification of the nuclear and nucleolar localization signals of the protein p120. Interaction with translocation protein B23". J. Biol. Chem. 269 (38): 23776–83. PMID 8089149.