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{{Infobox_gene}}
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'''Nucleophosmin''' (NPM), also known as '''nucleolar phosphoprotein B23''' or  '''numatrin''', is a [[protein]] that in humans is encoded by the ''NPM1'' [[gene]].<ref name="pmid8471164">{{cite journal | vauthors = Liu QR, Chan PK | title = Characterization of seven processed pseudogenes of nucleophosmin/B23 in the human genome | journal = DNA Cell Biol. | volume = 12 | issue = 2 | pages = 149–56 |date=March 1993 | pmid = 8471164 | doi = 10.1089/dna.1993.12.149| url =  }}</ref><ref name="pmid8122112">{{cite journal | vauthors = Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT | title = Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma | journal = Science | volume = 263 | issue = 5151 | pages = 1281–4 |date=March 1994 | pmid = 8122112 | doi = 10.1126/science.8122112| url = http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8122112 }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image = PBB_Protein_NPM1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2p1b.
| PDB = {{PDB2|2p1b}}
| Name = Nucleophosmin (nucleolar phosphoprotein B23, numatrin)
| HGNCid = 7910
| Symbol = NPM1
| AltSymbols =; B23; MGC104254; NPM
| OMIM = 164040
| ECnumber = 
| Homologene = 87629
| MGIid = 3647121
| GeneAtlas_image1 = PBB_GE_NPM1_221691_x_at_tn.png
| Function = {{GNF_GO|id=GO:0003713 |text = transcription coactivator activity}} {{GNF_GO|id=GO:0003723 |text = RNA binding}} {{GNF_GO|id=GO:0030957 |text = Tat protein binding}} {{GNF_GO|id=GO:0042803 |text = protein homodimerization activity}} {{GNF_GO|id=GO:0046982 |text = protein heterodimerization activity}} {{GNF_GO|id=GO:0051059 |text = NF-kappaB binding}} {{GNF_GO|id=GO:0051082 |text = unfolded protein binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005730 |text = nucleolus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005813 |text = centrosome}}
| Process = {{GNF_GO|id=GO:0006886 |text = intracellular protein transport}} {{GNF_GO|id=GO:0006913 |text = nucleocytoplasmic transport}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006950 |text = response to stress}} {{GNF_GO|id=GO:0007098 |text = centrosome cycle}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007569 |text = cell aging}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0042255 |text = ribosome assembly}} {{GNF_GO|id=GO:0051092 |text = activation of NF-kappaB transcription factor}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 4869
    | Hs_Ensembl = ENSG00000181163
    | Hs_RefseqProtein = NP_001032827
    | Hs_RefseqmRNA = NM_001037738
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 5
    | Hs_GenLoc_start = 170746725
    | Hs_GenLoc_end = 170770492
    | Hs_Uniprot = P06748
    | Mm_EntrezGene = 434373
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = XM_486188
    | Mm_RefseqProtein = XP_486188
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot =
  }}
}}
'''Nucleophosmin (nucleolar phosphoprotein B23, numatrin)''', also known as '''NPM1''', is a human protein and [[gene]]. It has attracted recent attention as a prognostic indicator in cytogenetically normal Acute Myelocytic Leukemia (CN-AML).  The NPM1-mutated AML encompasses all FAB / WHO catagories except FAB M3 (APL).  NPM1 gene mutations are found only in primary AML and not in AML arising from myelodysplasia (MDS; secondary AML). 
NPM1 gene mutations are most common in AMLs with monocytic differentiation (FAB M4/M5).  NPM1 mutations have a distinctive gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. 
NPM1 mutated AML is preferentially associated with AML with monocytic differentiation (inparticular FAB M5b), lack of CD34, normal cytogenetics, FLT3 gene mutations and a trend toward a favorable clinical outcome especially in patients without the FLT3 gene mutation. NOM1 gene mutations cause a frame shift in the C-terminus of exon 12, disrupting the NPM nucleolar-localization signal or generating a leucine-rich nuclear export motif, resulting in abnormal cytoplasmic accumulation of NPM. 


'''Genetics;'''
NPM1 is associated with [[Nucleolus|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 [[ribosome]]s 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.
The prevalence of cytogenetically-normal AML (CN-AML) varies between 40-49% of adults with de novo AML. Over half of the CN-AML patients can have the NPM1 mutation.  The NPM1 gene is mapped to chromosome 5q15.  NPM1 mutations cause alterations in the encoded protein that lead to its aberrant cytoplasmic localization.  Mutations in nucleophosmin NPM1 are the most frequently ACQUIRED molecular abnormality in AML. NPM1 mutations positively correlate with AML with a high WBC count, normal karyotype and fms-tyrosine kinase 3 gene (FLT3)  internal tandem duplication (ITD)mutations.  FLT3ITD is a secondary genetic alteration that is not stable over the course of the disease.  It is thoguht that the FLT3 "nullifies" the increased survival brought on by the presence of the NPM1.  These mutations may contribute to leukemogenesis at least in part through disruption of the MDM2-p53 pathway and centrosome duplication.


CN-AML can be divided into two subsets; one is a molecular low risk group (ie CN-AML with NPM1 and NO FLT3ITD) which has a better outcome and the other is the molecular high risk group (ie patients with FLT3ITD or those without FLT3ITD and WITH wild-type, non-mutated NPM1).  The event free survival (EFS) at 5 years is ~50% in patients with FLT3ITD negative / NPM1 mutated and only ~25% in patients with FLT3ITD positive / NPM1 wild-type (wt).  The former have been considered to be a molecular low risk group and the latter a molecular high risk group.  It has been shown that intermediate cytogenetic risk AML patient without FLT3ITD mutations but with NPM1 mutations have a significant better overall survival (OS) and EFS than those without NPM1 mutations.  In multivariate analyses NPM1 mutations express an independent prognostic value with regeard to OS, EFS and disease free survival (DFS).  In CN-AML patients older than 60 years the NPM1 mutation showed a higher complete response rate (CR) and had a significant increase in the OS compared with wild-type patients (84% versus 48%).   
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]].


Patients who have NPM1 and lack FLT3ITD also have a high expression of a gene called ERG and have a negative outcome similar to molecular high risk patients.  In contrast, patients who have NPM1+ and lack FLT3ITD would have a very favorable outcome if they express low levels of ERG. 
Nucleophosmin has multiple functions:<ref name="pmid21152184">{{cite journal | author = Lindström MS | title = NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling | journal = Biochem Res Int | volume = 2011 | issue = | pages = 195209 | year = 2011 | pmid = 21152184 | pmc = 2989734 | doi = 10.1155/2011/195209 | url = }}</ref>
# Histone [[Chaperone (protein)|chaperones]]
# Ribosome biogenesis and transport
# Genomic stability and DNA repair
# Endoribonuclease activity
# [[Centrosome]] duplication during cell cycle
# Regulation of ARF-p53 tumor suppressor pathway
# RNA helix destabilizing activity
# Inhibition of caspase-activated DNase
# Prevents apoptosis when located in nucleolus


'''Mechanism;'''
== Clinical significance ==
The various NPM1 mutations identified in AML are heterozygous and involve the C-terminal region encoded by exon 12.  These not only disrupt key tryptophan residues that are required for localization to the nucleolus, but also generate a nuclear export signal leading to delocalization of mutant NPM1 to the cytoplasm where it sequesters residual wild-type protein from the nucleus.  It is also thought to play an important role in centrosome assembly and has RNA binding and chaperone activity.  NPM1-mutated AMLs frequently have CD34-negative blasts, normal karyotype and have a good response to induction treatment.  NPM1 is predominantly localized in the nucleolus and is thought to function as a molecular chaperone of proteins, facilitating the transport of ribosomal proteins through the nuclear membrane.  Disruption of NPM1, either by chromosomal translocation or b mutation, results in the cytoplasmic dislocation of NPM1.  The high frequency of NPM1 mutations in AML with normal karyotypes and the observation that cytoplasmic NPM1 cannot exert its normal function as binding partner and transporter protein leads to the notion that NPM1 mutation may be an early event in leukemogenesis. 
Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor suppressor pathway.  Tranlocations involving the NPM gene cause cytoplasmic dislocation of the NPM protien. 


The granulocytic, monocytic, erythroid and megakaryocytic series were found to be involved and these findings are consistent with the NPM1 mutation arising in myeloid or multipotent progenitors and raise the distinct possibility that this may be a primary lesion in AML, present in the leukemic stem cell population. NPM1-mutated / FLT3-ITD negative cases show a better prognosis (overall response and better response to induction treatment) reinforcing the concept that NPM1 mutation is a founder genetic lesion.  Moreover, in cases where NPM1 and FLT3 are both mutated, multiple FLT3 internal tandem duplications (ITDs) can be detected within the leukemic subpopulations on the background of a single NPM1 mutation, implying that the latter was the first lesion to arise.  A high frequency of NPM1 gene mutations are found in blasts that have a prominent nuclear invagination, a so-called 'cup-like' nuclei.
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]].<ref name="pmid17488663">{{cite journal | vauthors = Falini B, Nicoletti I, Bolli N, Martelli MP, Liso A, Gorello P, Mandelli F, Mecucci C, Martelli MF | title = Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias | journal = Haematologica | volume = 92 | issue = 4 | pages = 519–32 |date=April 2007 | pmid = 17488663 | doi = 10.3324/haematol.11007| url = http://www.haematologica.org/cgi/pmidlookup?view=long&pmid=17488663 }}</ref> 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.


Chimeric oncoproteins generated as a result of the recurrent cytogenetic abnoramlities include t(8;21) / AML1-ETO, inv(16) / CBFB-MYH11 and t(11;23) / MLL rearrangements. The internal tandem duplication (ITD) in the fms-like tyrosine kinase-3 gene (FLT3) and the partial tandem duplication (PTD) of the mixed lineage leukemia gene (MLL) are indicative of a poor prognosis.
Of high importance is NPM involvement in [[acute myelogenous leukemia]],<ref name="MeaniAlcalay2014">{{cite journal|last1=Meani|first1=Natalia|last2=Alcalay|first2=Myriam|title=Role of nucleophosmin in acute myeloid leukemia|journal=Expert Review of Anticancer Therapy|volume=9|issue=9|year=2014|pages=1283–1294|issn=1473-7140|doi=10.1586/era.09.84}}</ref>
  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.


Immunopehnotypic analysis by flow cytometry has shown frequent absence of hematopoietic stem cell markers (CD34 and CD133) in NPM1-mutated AML (~80% versus 40% of cases lacking CD34 in NPM1-unmutated AML) while retaining other myeloid antigen markers such as CD13 and CD33.  NPM1 mutations are a sensitive marker for minimal residual disease.   
==Interactions==
NPM1 has been shown to [[Protein-protein interaction|interact]] with
* [[AKT1]],<ref name="pmid18931307">{{cite journal | vauthors = Lee SB, Xuan Nguyen TL, Choi JW, Lee KH, Cho SW, Liu Z, Ye K, Bae SS, Ahn JY | title = Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 43 | pages = 16584–9 |date=October 2008 | pmid = 18931307 | pmc = 2569968 | doi = 10.1073/pnas.0807668105 | url = }}</ref>
* [[BARD1]],<ref name=pmid15184379/>
* [[BRCA1]],<ref name="pmid15184379">{{cite journal | vauthors = Sato K, Hayami R, Wu W, Nishikawa T, Nishikawa H, Okuda Y, Ogata H, Fukuda M, Ohta T | title = Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase | journal = J. Biol. Chem. | volume = 279 | issue = 30 | pages = 30919–22 |date=July 2004 | pmid = 15184379 | doi = 10.1074/jbc.C400169200 | url =  }}</ref> and
* [[nucleolin]].<ref name="pmid8620867">{{cite journal | vauthors = Li YP, Busch RK, Valdez BC, Busch H | title = C23 interacts with B23, a putative nucleolar-localization-signal-binding protein | journal = Eur. J. Biochem. | volume = 237 | issue = 1 | pages = 153–8 |date=April 1996 | pmid = 8620867 | doi = 10.1111/j.1432-1033.1996.0153n.x | url = }}</ref>


With regards to bone marrow transplantation if a patient had mutant NPM1 without FLT3ITD then there was no apparent advantage for transplantation in the first remission because, by analysis, for patients with NPM1-mutated / FLT3 wild-type, the relapse free survival (RFS) was the same regardless of whether or not a donor was available.  If the patient had any genotype other than NPM1-mutated / FLT-wild type there was a definite benefit to receiving the allogeneic transplantation or at least having the donor and the potential for transplantation while in first remission. 
Nucleophosmin has multiple binding partners:<ref name="pmid21152184"/>
# rRNA
# HIV Rev and Rex peptide
# p53 tumor suppressor
# ARF tumor suppressor
# MDM2 (mouse double minute 2, ubiquitin ligase)
# Ribosome protein S9
# Phosphatidylinositol 3,4,5-triphosphate (PIP3)
# Exportin-1 (CRM1, chromosome region maintenance)
# Nucleolin/C23
# Transcription target of myc oncogene


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

Revision as of 20:27, 8 November 2017

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Identifiers
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Nucleophosmin (NPM), also known as nucleolar phosphoprotein B23 or numatrin, is a protein that in humans is encoded by the NPM1 gene.[1][2]

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:[3]

  1. Histone chaperones
  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.[4] 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,[5] 

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

Nucleophosmin has multiple binding partners:[3]

  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. ↑ 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.
  2. ↑ 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.
  3. ↑ 3.0 3.1 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 7.0 7.1 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.
  8. ↑ 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

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