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NPM1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNPM1, B23, NPM, nucleophosmin (nucleolar phosphoprotein B23, numatrin), nucleophosmin, nucleophosmin 1
External IDsOMIM: 164040; MGI: 106184; HomoloGene: 81697; GeneCards: NPM1; OMA:NPM1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4869

18148

Ensembl

ENSG00000181163

ENSMUSG00000057113

UniProt

P06748

Q61937

RefSeq (mRNA)

NM_001252260
NM_001252261
NM_008722

RefSeq (protein)

NP_001239189
NP_001239190
NP_032748

Location (UCSC)Chr 5: 171.39 – 171.41 MbChr 11: 33.1 – 33.11 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Nucleophosmin (NPM), also known as nucleolar phosphoprotein B23 or numatrin, is a protein that in humans is encoded by the NPM1 gene.[5][6]

Discovery

[edit]

NPM1 was first discovered as a nucleolar phosphoprotein in rat liver cells and Novikoff hepatoma ascites cells.[7][8] It was named B23 as it was the 23rd spot in the B section of the 2-D gel where spots were numbered in the order of decreasing mobility. It was named numatrin independently by another group as it was found to be tightly associated with the nuclear matrix and its expression was induced upon mitogenic signals in human B lymphocytes.[9][10] At around the same time, the Xenopus NO38 was discovered and was found to be homologous to Xenopus Nucleoplasmin and rat B23.[11]

Gene

[edit]

In humans, the NPM1 gene is located on the long arm of chromosome 5 (5q35). The gene spans 23 kb and contains 12 exons. Three transcript variants have been described. The longest isoform (294 amino acids long), encoded by transcript variant 1, is the major and the most well studied isoform of Nucleophosmin. Transcript variant 2 is produced by skipping an in-frame exon (exon 8) to produce an isoform that is 265 amino acids long. However, this isoform is not well characterized and its functions and expression pattern is not well understood. Transcript variant 3 is produced by using an alternate exon (exon 10) which results in an isoform 259 amino acids long with a different C-terminal sequence. The isoforms 1 and 3 of human NPM1 are B23.1 and B23.2 respectively in rat.[12] The isoform 1 is localized to the nucleolus[13] as is reported for rat B23.1[14][15] whereas the isoform 3 (B23.2) is nucleoplasmic or cytoplasmic in localization and is expressed at relatively lower levels as compared to isoform 1 in normal rat tissues[16] and in HeLa cells.[13] Both isoforms 1 and 3 have been shown to stimulate the replication of adenoviral DNA complexed with viral basic proteins.[13]

Structure

[edit]

The NPM1 protein can be divided into several domains with sequence motifs that are conserved across nucleoplasmin family and have important and distinct functions. The N-terminal core domain, the acidic stretches, basic domain and the aromatic nucleic acid domain make up the NPM1 protein. Further, sequence motifs such as the nuclear export signals (NES), nuclear localization signals (NLS) and the nucleolar localization signals (NoLS) are critical for the localization of NPM1 to the nucleolus as well as its nucleo-cytoplasmic shuttling required for its diverse array of functions.

The N-terminal domain also known as the core domain (residues 1-119 of human NPM1) is the most conserved domain among the NPM family proteins. This domain folds into a distinct structure that is protease resistant and is responsible for the oligomerization and chaperone activity of these proteins. It contains several hydrophobic residues that are highly conserved (~80%) among NPM proteins. The crystal structure of NPM1 core domain (residues 9-122) shows that this domain folds into an eight stranded β-barrel with jelly roll topology forming a wedge shaped hydrophobic core that fits snugly to form a pentamer through hydrophobic interactions between the monomeric subunits. Two pentameric complexes align in a head to head fashion to form the decameric structure. A comparison between the crystal structure of human NPM1 and that of the core domains of Xenopus NO38, Xenopus Nucleoplasmin and Drosophila Nucleoplasmin like protein (dNLP) show that both the monomeric and pentameric structures are highly similar among all the NPM family proteins. The human NPM1 core domain (residues 15-118) shares a sequence identity of 80%, 51% and 29% with Xenopus NO38, Nucleoplasmin and Drosophila NLP cores respectively. All of them form the same β barrel structure with jelly roll topology.

NPM1 was speculated to be a hexamer under native conditions since it was found to have a molecular weight of 230–255 kDa calculated by gel filtration chromatography and sedimentation analyses. However, the crystal structure of the NPM1 core clearly shows that it is a pentamer. The pentamer-pentamer interface consists of several water molecules involved in hydrogen bonding between the two pentamers. Moreover, ten charge based interactions between the Asp of the highly conserved AKDE loop and Lys82 give additional stability. Comparison of dNLP and Nucleoplasmin structures has revealed that formation of the decamer might be facilitated by histone binding. The H2A-H2B dimer may bind to the lateral surface of the NPM1 decamer. Furthermore, comparison of the crystal structures of human NPM1 and Xenopus NO38 reveals structural plasticity in the pentamer-pentamer interface. When one of the pentamers of human NPM1 and Xenopus NO38 are superimposed, there is a large rotational offset (~20°) between the other pentamers. Further, the direction of the rotational offsets are opposite for human NPM1 and Xenopus NO38 when compared to Xenopus Nucleoplasmin core structure. The significance of this structural plasticity is not well understood, however, it may have a significance in the chaperone function of NPM1.

Function

[edit]

NPM1 is associated with nucleolar ribonucleoprotein structures and binds 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 protein'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 was identified as a phosphoprotein. However, later other post-translational modifications for NPM1 were identified including acetylation and SUMOylation.

Nucleophosmin has multiple functions:[17]

  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

Molecular and histone chaperone

[edit]

NPM1 functions as a molecular chaperone for several proteins. Both the N-terminal hydrophobic core domain and acidic stretches are important for this activity. Furthermore, oligomerization of NPM1 has been shown to be necessary for maximum chaperone activity.[18] NPM1 has been predicted to play a role in preventing protein aggregation in the densely packed nucleolus especially during ribosome biogenesis. NPM1 shows characteristic properties of molecular chaperones such as a) preventing temperature dependent and independent aggregation of proteins, b) preserving enzyme activities during thermal denaturation of several different proteins, c) promoting the renaturation of previously denatured proteins, d) preferentially binding to denatured proteins, and exposing hydrophobic regions during interaction with other proteins. NPM1 can bind to ATP,[19] yet, its chaperoning function does not require ATP hydrolysis or the presence of ATP.[20]

NPM1 is known to associate with pre-ribosomal particles and other nucleolar proteins. Since ribosomal proteins tend to be insoluble under physiological conditions, NPM1 presumably binds to ribosomal proteins in the nucleolus, prevent them from aggregation and promote their assembly into the ribosomal subunits. Similarly, certain viral proteins such as HIV-1 Rev that are insoluble under physiological conditions, bind to NPM1 which prevents their aggregation and allows their accumulation in the nucleus/nucleolus thereby promoting viral particle assembly. Further, since NPM1 can shuttle between the nucleus and the cytoplasm[21] by virtue of its NES and NLS, it could help in co-translational folding of client proteins in the cytoplasm and promote their entry into the nucleus/nucleolus.[20]

NPM1 is a highly acidic protein and can bind to histones directly because of their basic nature. NPM1 binding to histones is retained even at a salt concentration of 0.5 M KCl suggesting a strong binding with the help of electrostatic interactions.[22] However, electrostatic interactions alone are not responsible for binding to histones as is suggested by the NPM1 core crystal structure. NPM1 directly binds to core histones H2B, H3 and H4 and can bind to H2A only in the presence of the H2A-H2B dimer or the core histone octamer. It can assemble nucleosomes in vitro and can decondense sperm chromatin similar to nucleoplasmin.[23][24][22] NPM1 histone chaperone activity has been suggested to be involved in nucleosome disassembly during transcription resulting in activation of transcription.[22] It is also presumed to function as a histone chaperone in the nucleolus.[25] Depletion of NPM1 or overexpression of a mutant NPM1 lacking histone chaperone activity leads to a decrease in rDNA transcription.[26] It can also bind to linker histone H1 and promote its assembly or disassembly from chromatin.[27]

Ribosome biogenesis

[edit]

NPM1 is a molecular chaperone.[20] It was also observed to associate with preribosomes, hence it was initially thought that NPM1 is a ribosome assembly factor or a ribosome chaperone.[28] Other characteristic properties that suggest NPM1 role in ribosome biogenesis are nucleolar localization, ability to shuttle between the nucleus and cytoplasm, ability to bind to nucleic acid and to transport pre-ribosomal particles.[21][29][30][31][32] NPM1 also has an intrinsic ribonuclease activity that cleaves a specific site in the ITS2 (Internal transcribed spacer 2) of the pre-5.8S rRNA.[33][34] Knockdown of NPM1 leads to changes in the profiles of ribosomes. (Grisendi et al., 2005) Degradation of NPM1 induced by ARF leads to defects in the processing of pre-ribosomal RNA from the 32S precursor rRNA to the 28S rRNA species (Itahana et al., 2003). Moreover, blocking the NPM1 nucleo-cytoplasmic shuttling inhibits ribosome subunit export resulting in a decrease in the cell growth rate showing that NPM1 exports pre-ribosomes (Maggi et al., 2008). Furthermore, NPM1 interacts with a number of ribosomal proteins including RPL5 (Yu et al., 2006), RPS9 (Lindström and Zhang, 2008) and RPL23 (Wanzel et al., 2008). NPM3 was shown to bind to NPM1 and negatively regulate ribosome biogenesis whereas an NPM1 binding defective mutant of NPM3 did not have any effect on ribosome biogenesis (Huang et al., 2001). Interestingly, NPM1 isoform 3 that does not have a nucleic acid binding domain also inhibits ribosome biogenesis. All these findings suggest an important role of NPM1 in ribosome biogenesis.

Most cancer cells have enlarged nucleoli and the aberrant overexpression of NPM1 has been correlated well with the increased ribosome biogenesis in highly proliferating cells. Thus NPM1 by controlling ribosome biogenesis could control the proliferative rate of cells. NPM1 knockout mouse embryos survive upto mid-gestation (9.5dpc-12.5dpc) (Colombo et al., 2005; Grisendi et al., 2005), whereas, knockout of pescadillo, a protein involved in ribosome biogenesis, leads to death of the embryos at morula stages (2.5 dpc) (Lerch-Gaggl et al., 2002). This suggests that either NPM1 may not be essential for ribosome biogenesis, as other proteins could have overlapping functions with NPM1 or there could be other factors such as ribosome storage in oocytes that could have compensated for the loss of NPM1 in NPM1 null embryos (Grisendi et al., 2006).

Role in transcriptional regulation

[edit]

NPM1 has been shown to be an important co-activator for RNA Polymerase II driven transcription. Acetylation of NPM1 enhances this activity through increased histone binding and chaperone activity.[22] Intriguingly acetylated NPM1 (AcNPM1) is a distinct pool localized in the nucleoplasm in contrast to the nucleolar localization of unmodified and phosphorylated NPM1.[35] Genome-wide profiling of AcNPM1 occupancy by ChIP-sequencing reveals that it localizes to the transcription start site of many gene promoters and is co-occupied with RNA Polymerase II.[36]

Clinical significance

[edit]

The 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.[37] 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,[38] 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, and is associated with improved clinical outcomes. 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. It has also been shown that in the context of clonal hematopoiesis of undetermined significance harboring a DNMT3A mutation, subsequent NPM1 mutations drive progression into overt myeloproliferative neoplasm.[39]

In addition, NPM1 is overexpressed in many solid tumors including gastric, colon, breast, ovary, bladder, oral, thyroid, brain, liver, prostate cancer and multiple myeloma. NPM1 overexpression correlates well with the clinical features of hepatocellular carcinoma suggesting that NPM1 overexpression could serve as a diagnostic marker for hepatocellular carcinoma. NPM1 overexpression and hyperacetylation progresses according to the increasing grade of tumor in OSCC.[35] NPM1 overexpression also correlates well with recurrence and progression of bladder cancer to advanced stages. NPM1 overexpression is associated with acquired oestrogen-independence in human breast cancer cells (Skaar et al., 1998). Moreover, NPM1 is a direct transcriptional target of oncogenic transcription factor c-myc (Zeller et al., 2001). The ability of NPM1 to suppress apoptosis and promote DNA repair might be responsible for the survival of tumor cells where NPM1 is overexpressed. All these studies suggest that NPM1 overexpression promotes tumor development and hence could function as a proto-oncogene.

Interactions

[edit]

NPM1 has been shown to interact with

Nucleophosmin has multiple binding partners:[17]

  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

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

NPM1

View on Grokipedia
from Grokipedia
Nucleophosmin 1 (NPM1), also known as B23 or numatrin, is a highly conserved, ubiquitously expressed encoded by the NPM1 on 5q35.1 in humans. This 294-amino-acid protein, with a molecular weight of approximately 37 , primarily localizes to the of proliferating cells, where it functions as a molecular chaperone involved in essential cellular processes such as , assembly, and centrosome duplication. NPM1 shuttles dynamically between the , nucleoplasm, and , enabling its multifaceted roles in maintaining cellular and responding to stress. Structurally, NPM1 features an N-terminal oligomerization domain that facilitates its assembly into pentameric or decameric complexes, a central acidic region for binding histones and other acidic proteins, and a C-terminal domain rich in aromatic and basic residues that interacts with nucleic acids and ATP. These domains allow NPM1 to exhibit chaperone-like activity, preventing and aiding in the transport of ribosomal components from the nucleus to the . Post-translational modifications, including , , and sumoylation, regulate its localization and function, with particularly influencing its nucleolar retention during . Beyond its structural roles, NPM1 participates in a wide array of cellular functions, including the regulation of p53-mediated through interactions with tumor suppressors like ARF and , as well as contributions to DNA damage repair pathways such as and . It also supports , mRNA processing, and embryogenesis, underscoring its importance in both normal development and stress responses. In proliferating cells, NPM1 is one of the most abundant proteins in the , highlighting its pivotal role in nucleolar architecture and assembly. Dysregulation of NPM1 is strongly implicated in oncogenesis, with mutations occurring in approximately 30% of (AML) cases, often leading to aberrant cytoplasmic localization (NPM1c+) that disrupts its tumor-suppressive functions and promotes leukemogenesis. Overexpression of NPM1 has been observed in various solid tumors, including , , and gastric cancers, where it acts as a proto-oncogene by enhancing cell survival and proliferation. Conversely, NPM1 can function as a tumor suppressor in certain contexts, such as by stabilizing ; its genetic alterations, including translocations like NPM1-ALK fusions in lymphomas, further underscore its dual role in hematological and solid malignancies.

Discovery and Nomenclature

Initial Identification

NPM1 was first identified as a major nucleolar protein in 1973 through two-dimensional of nucleolar extracts from normal rat liver and Novikoff hepatoma ascites cells, where it appeared as a prominent acidic spot indicative of high abundance in proliferating cells. This technique separated over 100 nucleolar proteins, highlighting NPM1 (later named B23 based on its position as the 23rd spot in the gel pattern) as one of the most abundant components, comprising up to 0.5% of total cellular protein in tumor cells. The protein was subsequently characterized as a in 1974 via radiolabeling with [^{32}P]orthophosphate in Novikoff hepatoma cells, revealing its by nuclear kinases. In the early 1980s, further experiments using cells confirmed NPM1's high abundance and dynamic through radiolabeling studies and . NPM1 constitutes approximately 20 times more protein in exponentially growing cells compared to quiescent ones. Key experiments demonstrated cell cycle-dependent , with increased labeling during /M phases, suggesting regulatory roles in nucleolar function tied to proliferation. These findings established NPM1 as a major nucleolar phosphoprotein, initially termed B23, with its alternative name numatrin assigned in 1988 following identification as a substrate for casein kinase II. Early observations of NPM1's nucleocytoplasmic shuttling emerged in the late 1980s and early 1990s, particularly in response to cellular stress and viral infections. For instance, treatment of HeLa cells with actinomycin D induced translocation of NPM1/B23 from the nucleolus to the nucleoplasm and cytoplasm, indicating stress-responsive mobility. Similar shuttling was noted in HL-60 cells treated with iron chelators like deferoxamine, as well as during viral infections, such as with adenovirus, where NPM1 facilitated viral DNA replication by moving to the cytoplasm to interact with viral components. These initial biochemical characterizations laid the groundwork for later molecular studies on gene cloning.

Gene Cloning and Naming

The human NPM1 gene was cloned in 1989 through screening of a λgt11 cDNA expression derived from human placenta, yielding a full-length cDNA sequence of 1.3 kb that encodes a 294-amino-acid protein. This cloning effort identified the gene as encoding nucleophosmin, a nucleolar previously known from protein studies, and established early aliases such as and B23. Subsequent analyses in the early further characterized related pseudogenes but confirmed the primary cDNA sequence's integrity. The official Human Genome Nomenclature Committee (HGNC) symbol for the gene, NPM1, was approved to standardize its designation, distinguishing it from related family members, with the full name nucleophosmin 1. Synonyms approved by HGNC include B23, , nucleolar phosphoprotein B23, and numatrin, reflecting its historical identification as a major nucleolar protein. Early chromosomal mapping of NPM1 to 5q35 was achieved in 1994 using (FISH) on chromosomes from patients with anaplastic large cell carrying the t(2;5)(p23;q35) translocation, which fuses NPM1 to the ALK gene on 2p23. This localization was corroborated by analysis of hybrids, confirming the gene's position in the 5q35 region.

Gene Characteristics

Genomic Organization

The NPM1 is located on the long arm of at cytogenetic band 5q35.1, with genomic coordinates spanning from 171,387,116 to 171,411,810 on the GRCh38 reference assembly, encompassing approximately 24.7 kb of DNA. This includes 11 exons in its canonical transcript, with the full gene utilizing 12 exons across all isoforms as annotated in reference databases. The canonical isoform, NPM1.1 (also known as B23.1), is generated through the splicing of 11 exons (skipping exon 10), with exon lengths varying from 58 bp to 358 bp, producing a mature mRNA of about 1.3 kb that encodes a 294-amino-acid protein. Exon-intron boundaries adhere to the consensus splice site motifs, primarily GT at the 5' donor sites and AG at the 3' acceptor sites, ensuring precise removal of 10 introns during pre-mRNA processing; introns range in size from several hundred base pairs to over 5 kb, contributing to the overall genomic span. This splicing pattern defines the full-length NPM1.1 transcript (NM_002520.7), which includes untranslated regions flanking the coding sequence. NPM1 exhibits strong evolutionary conservation across mammalian species, reflecting its essential roles in cellular processes. The ortholog, Npm1, shares approximately 86% sequence identity with human NPM1 in the protein-coding regions, while orthologs in other mammals such as and show even higher similarity exceeding 90% in conserved domains. This high degree of sequence identity underscores the functional importance of NPM1's genomic architecture from to .

Expression Regulation

The NPM1 gene exhibits ubiquitous expression across various normal human tissues, reflecting its essential roles in fundamental cellular processes such as and protein chaperoning. Expression levels are particularly elevated in proliferating tissues, including and , where NPM1 supports active and growth. This pattern aligns with NPM1's higher abundance in rapidly dividing cells compared to quiescent ones, underscoring its association with . At the transcriptional level, NPM1 expression is governed by a TATA-less promoter lacking a TATA box, which relies on alternative initiation mechanisms for basal activity. Key regulatory elements within this promoter include multiple Sp1 binding sites in the upstream region, which facilitate recruitment and enhance promoter activity in proliferating cells. The promoter's cell cycle-dependent nature contributes to upregulated NPM1 transcription during phases of active proliferation, such as , ensuring sufficient protein levels for nucleolar functions. Additional upstream elements, like AP-1 and YY1 sites, further modulate this regulation in response to growth signals. Post-transcriptional control of NPM1 involves microRNA-mediated repression, where miRNAs bind to the 3' (3' UTR) of the mRNA to inhibit or promote degradation. For instance, miR-337-5p targets the NPM1 3' UTR, fine-tuning expression levels in hematopoietic cells to prevent overexpression during steady-state conditions. Such mechanisms help maintain balanced NPM1 protein availability in normal tissues. NPM1 produces multiple isoforms through of its 12 exons, with NPM1.1 (also known as R1 or B23.1) being the predominant variant in normal cells, accounting for the majority of transcripts and exhibiting nucleolar localization. Minor isoforms, such as R2 (B23.2), arise from exclusion of exons 11 and 12, resulting in altered C-terminal domains that shift localization to the nucleoplasm or , potentially modulating isoform-specific functions in proliferating compartments like . These variants are expressed at low levels in normal tissues but contribute to regulatory diversity without disrupting overall NPM1 .

Protein Structure

Domain Composition

NPM1, also known as nucleophosmin, is a 294-amino acid protein with a calculated molecular weight of 32.6 , although it typically appears at approximately 37 on due to its highly phosphorylated state. The protein exhibits an overall acidic character, consistent with its domain composition rich in negatively charged residues. The N-terminal oligomerization domain spans residues 1–120 and forms the core folded region of NPM1, enabling pentamer assembly through hydrophobic interfaces that contribute to the protein's . This domain also incorporates two nuclear export signals (NES) at positions 42–49 and 94–102, which are embedded within the sequence to regulate subcellular localization. Adjacent to the N-terminal domain lies the central acidic domain, encompassing residues 118–125 (part of broader acidic tracts from 119–133 and 161–188), a negatively charged region composed primarily of aspartic and glutamic acid residues that imparts electrostatic properties suitable for histone interactions. The C-terminal nucleic acid-binding domain, covering residues 243–294, is an arginine-rich motif that adopts a three-helix bundle structure, facilitating non-specific binding to RNA and DNA. This domain includes a nucleolar localization signal (NoLS) defined by tryptophan residues at positions 288 and 290.

Oligomerization and Modifications

NPM1 primarily assembles into symmetric pentamers through interactions mediated by its N-terminal oligomerization domain, which forms a stable β-barrel structure stabilized by hydrophobic contacts and hydrogen bonds at the protomer interfaces. This pentameric configuration predominates under physiological conditions, exhibiting high-affinity assembly with dissociation constants in the nanomolar range, ensuring robust oligomerization in the nucleolar environment. The N-terminal domain's structural polymorphism allows flexibility, but the wild-type pentamer remains tightly associated, contributing to NPM1's multivalent interactions within the nucleolus. Post-translational modifications dynamically regulate NPM1's oligomerization, localization, and activity. at Ser125, catalyzed by CDK1 and Aurora B during , occurs within the N-terminal domain and promotes partial dissociation of the pentamer, facilitating NPM1's redistribution from the to the nucleoplasm and centrosomes. at multiple residues (e.g., Lys212, Lys215, Lys229, Lys230, Lys257, Lys267, Lys292) by p300 acetyltransferase enhances NPM1's association with transcriptionally active in the nucleoplasm, while unacetylated forms favor nucleolar retention through preserved oligomerization and interactions with nucleolar components. Additionally, SUMOylation at Lys263, induced under cellular stress conditions, modulates NPM1's subcellular localization and supports survival pathways by altering its binding affinities and shuttling dynamics. NPM1's nucleocytoplasmic shuttling is governed by a balance between nuclear import and export mechanisms influenced by its modifications. The N-terminal nuclear export signals (NES) interact with CRM1 (exportin-1) to mediate CRM1-dependent nuclear export, allowing NPM1 to traffic to the . Conversely, nuclear import is facilitated by a bipartite nuclear localization signal (NLS) in the central domain (residues 141-157), which binds α/β heterodimers to enable into the nucleus. and other modifications fine-tune this equilibrium, with mitotic enhancing export and nucleolar retention signals promoting import and accumulation in the .

Cellular Functions

Chaperone Activities

Nucleophosmin (NPM1) functions as a chaperone, primarily interacting with core H3 and H4 to prevent their aggregation and facilitate the assembly of H3-H4 tetramers essential for formation and . The central region of NPM1 contains acidic patches (AD2 and AD3) that mediate binding to the basic histone tails, shielding them from non-specific interactions and aggregation under physiological conditions. This binding is crucial during , where NPM1 ensures the faithful inheritance of parental , including repressive marks like , by coordinating with replication factors such as MCM2 and the Polycomb repressive complex 2 (PRC2). Depletion of NPM1 leads to disrupted assembly and altered , underscoring its role in maintaining integrity. In addition to its histone-specific functions, NPM1 exhibits general molecular chaperone activity in the , assisting in the proper folding and stability of client proteins such as and p14ARF, particularly under cellular stress conditions like heat shock. By sequestering these proteins in the , NPM1 prevents their misfolding and degradation; for instance, it inhibits MDM2-mediated ubiquitination of , thereby enhancing stability and promoting stress-induced responses such as or . Similarly, NPM1 acts as a nucleolar reservoir for p14ARF, regulating its release to modulate activity during oncogenic stress. These interactions highlight NPM1's protective role against proteotoxic stress in the . The chaperone mechanism of NPM1 is ATP-independent, relying on its oligomeric structure—primarily pentameric assemblies formed by the N-terminal domain—to create a hydrophobic shield via the C-terminal domain and acidic intrinsically disordered regions. This architecture traps aggregation-prone hydrophobic regions of client proteins, preventing misfolding. assays demonstrate NPM1's efficacy in retarding formation, such as delaying Aβ42 fibrillation in a dose-dependent manner, and protecting denatured proteins from aggregation, consistent with its role as a holdase chaperone. The central acidic domain, briefly referenced for enabling binding, contributes to this broader client recognition without requiring energy input.

Ribosome Biogenesis

Nucleophosmin 1 (NPM1), also known as B23, plays a critical role in by facilitating multiple stages of ribosomal subunit assembly within the . As an abundant nucleolar , NPM1 acts as a chaperone that supports the maturation of pre-ribosomal ribonucleoprotein (RNP) complexes, ensuring efficient production of functional and 60S subunits. Its involvement spans from pre-rRNA to the shuttling and integration of ribosomal proteins, ultimately contributing to the of nascent . Disruptions in NPM1 function, such as through depletion or , lead to defects in ribosome assembly, highlighting its indispensable nature in cellular proliferation and . In rRNA processing, NPM1 binds directly to pre-rRNA transcripts, associating with pre-ribosomal particles to promote their maturation. Specifically, NPM1 exhibits endoribonuclease activity that facilitates the cleavage of the 32S pre-rRNA to generate the mature 28S rRNA, a key step in 60S subunit formation. This enzymatic function is supported by its interaction with the pre-rRNA backbone, where NPM1 stabilizes intermediates and prevents degradation. Studies using (siRNA) knockdown demonstrate that NPM1 inhibition impairs this cleavage event, resulting in reduced levels of mature 28S rRNA and accumulation of processing intermediates. Although NPM1 primarily acts in later nucleolar stages, its binding supports the overall fidelity of rRNA maturation by coordinating with other nucleolar factors. NPM1 is essential for the nucleocytoplasmic shuttling of ribosomal proteins, enabling their import into the for incorporation into pre-ribosomal complexes. It directly interacts with small subunit ribosomal proteins (RPS), such as RPS9, as well as large subunit proteins like RPL5 and RPL23, facilitating their transport from the to the . For instance, NPM1 chaperones the 5S rRNA-RPL5 complex, utilizing its nuclear localization signals to mediate nucleolar accumulation and subsequent assembly into pre-60S particles. This shuttling is CRM1-dependent for export but relies on NPM1's oligomeric structure for efficient import. Once in the , NPM1 coordinates with nucleolar proteins (NOPs), including NOPP34 and PES1, to organize the hierarchical assembly of 40S and 60S subunits. These interactions ensure that ribosomal proteins are delivered in a timely manner to pre-rRNA scaffolds, preventing misassembly and supporting the maturation of both subunit types. Regarding quality control, NPM1 enforces checkpoints to prevent the export of immature or defective ribosomal subunits from the to the . By binding to pre-ribosomal RNPs, NPM1 stabilizes functional complexes while inhibiting the nuclear export of aberrant particles, thereby maintaining nucleolar integrity. Depletion studies reveal that loss of NPM1 leads to the accumulation of aberrant pre-40S particles, characterized by incomplete and improper protein incorporation, which triggers nucleolar stress and arrest. In NPM1 knockout mice, is severely compromised, resulting in hematopoietic defects and embryonic lethality between E11.5 and E12.5 due to insufficient mature ribosomes.

Transcriptional Regulation

Nucleophosmin 1 (NPM1) functions as a co-activator of the transcription factor, particularly through its interaction with the p65 (RelA) subunit. By binding to the N-terminal of p65, NPM1 enhances the recruitment of p65 to promoter regions of target genes, thereby promoting NF-κB-mediated transcriptional activation. This chaperone-like activity of NPM1 facilitates efficient DNA binding by reducing intramolecular interactions within p65, allowing better access for co-activators. In inflammatory contexts, such as TNF-α stimulation, NPM1 upregulation leads to increased expression of pro-inflammatory cytokine genes, including IL-6, IL-8, and TNF itself, with knockdown of NPM1 reducing their induction by over 1.5-fold in microarray analyses of cells. NPM1 exerts a suppressive effect on certain target genes, balancing activity to modulate apoptotic responses. Through direct binding to the N-terminal of , NPM1 inhibits 's transcriptional activity, particularly on pro-apoptotic genes, thereby antagonizing stress-induced in hematopoietic cells. This interaction prevents at key sites like Ser15 and suppresses the expression of downstream targets such as p21, as evidenced by reduced in NPM1-overexpressing cell lines exposed to . Additionally, NPM1 sequesters in the , inhibiting its activity toward and indirectly stabilizing levels, though this stabilization is contextually coupled with transcriptional inhibition to limit excessive apoptotic gene activation. As a histone chaperone, NPM1 contributes to chromatin remodeling by facilitating nucleosome disassembly and enhancing acetylation-dependent transcription. NPM1 directly binds core histones H3 and H4, promoting their acetylation by histone acetyltransferases like p300/CBP, which increases chromatin accessibility at transcription start sites. This activity supports RNA polymerase II-mediated transcription from chromatin templates in vitro, with NPM1 depletion leading to compacted heterochromatin and reduced expression of developmental genes like those in the Hox cluster. In vivo, NPM1's histone chaperone function aids in maintaining open chromatin states during cellular processes requiring transcriptional activation, without altering basal nucleosome assembly.

DNA Damage Response

Nucleophosmin (NPM1) plays a critical role in the DNA damage response by facilitating the recruitment of repair factors to sites of double-strand breaks (DSBs). Upon induction of DSBs, NPM1 is phosphorylated at threonine 199 (Thr199), enabling its accumulation at damage sites through interaction with RNF8- and RNF168-dependent conjugates. This recruitment occurs downstream of kinase activation, integrating NPM1 into the early signaling cascade that coordinates DSB repair and chromatin remodeling. NPM1's presence at DSB foci supports the formation of repair complexes, including those involving , thereby promoting and pathways. In addition to DSB repair, NPM1 contributes to translesion synthesis (TLS), a tolerance mechanism for bypassing DNA lesions that stall replication forks. NPM1 directly interacts with the catalytic domain of DNA polymerase η (Polη), stabilizing the enzyme and preventing its proteasomal degradation following UV-induced damage. This chaperone-like function enhances Polη-mediated TLS, allowing accurate bypass of cyclobutane pyrimidine dimers and reducing mutagenesis. Deficiency in NPM1 impairs TLS efficiency, leading to increased sensitivity to UV radiation and accumulation of replication stress. NPM1 also supports base excision repair (BER) by interacting with apurinic/apyrimidinic endonuclease 1 (APE1), a central enzyme in the pathway that processes oxidative and alkylative DNA lesions. The NPM1-APE1 complex enhances APE1's endonuclease activity, facilitating the removal of abasic sites and subsequent gap filling. In vivo, NPM1 knockdown sensitizes cells to BER-inducing agents like bleomycin, underscoring its role in maintaining genomic integrity against endogenous and exogenous genotoxins. Under , NPM1 undergoes nucleocytoplasmic shuttling, relocating to the where it participates in the assembly of phase-separated granules that resemble stress granules. These NPM1-enriched structures sequester and stabilize mRNAs encoding survival and repair factors, modulating translational repression to promote cell resilience. Recent studies further highlight NPM1's involvement in protecting stalled replication forks, primarily through its regulation of TLS and interactions with repair proteins, preventing fork collapse and genomic instability.

Protein Interactions

Key Binding Partners

Nucleophosmin 1 (NPM1) engages in direct interactions with several key proteins that modulate its roles in cellular , primarily through specific domain-mediated binding. These partnerships are often characterized by multivalent or transient affinities, facilitating dynamic nucleolar assembly and function. Prominent among these are tumor suppressors like and ARF, as well as regulators of protein stability and processing. NPM1 binds , stabilizing and enhancing its transcriptional activity in response to stress signals. This interaction inhibits p53 ubiquitination and degradation, with binding occurring in the under normal conditions and relocating to the nucleoplasm upon stress. Similarly, NPM1 interacts with ARF via its N-terminal oligomerization domain, where ARF's N-terminal domain engages acidic grooves on NPM1, promoting ARF's nucleolar retention and sequestration. These bindings are multivalent and of moderate affinity, typically in the micromolar range, enabling rapid disassembly during nucleolar stress. NPM1 also directly associates with , an E3 ubiquitin ligase, through interactions involving MDM2's N- and C-terminal regions, facilitating MDM2's nucleolar sequestration. This binding prevents MDM2-mediated ubiquitination, thereby supporting activation without altering MDM2's central domain. The interaction is enhanced under nucleolar stress, where NPM1 relocation disrupts the MDM2- complex. In , NPM1 binds ribosomal proteins such as RPS9 and RPL5, aiding their nucleolar import and assembly. These interactions were initially identified through two-hybrid screens, revealing multiple binding motifs on RPS9 that mediate nucleolar targeting. For RPL5, the binding supports pre-rRNA processing and 5S rRNA incorporation into ribosomes. Additional partners include upstream binding factor (UBF), where NPM1's association enhances rRNA transcription by stabilizing UBF on rDNA promoters. NPM1 also interacts with apurinic/apyrimidinic endonuclease 1 (APE1) via APE1's N-terminal lysine-rich region (residues 1-33), stimulating APE1's endonuclease activity in within nucleoli. Furthermore, NPM1 binds the HIV-1 Rev protein through its N-terminal and central domains (oligomerization and histone-binding regions), independent of , promoting Rev's nucleolar localization with a stoichiometry of one Rev per NPM1 pentamer.

Regulatory Networks

NPM1 serves as a central node in several regulatory networks that maintain cellular , integrating signals from nucleolar , mitotic progression, and stress response pathways. Through its dynamic localization and post-translational modifications, NPM1 coordinates responses to perturbations in and fidelity, often converging on tumor suppressor activation to prevent aberrant proliferation. Recent studies highlight NPM1's role in phase-separated condensates that facilitate interactions with partners like ARF and ribosomal proteins, enhancing nucleolar organization. In the nucleolar stress response network, NPM1 links disruptions in ribosomal biogenesis to -mediated arrest or . Under normal conditions, NPM1 resides primarily in the , facilitating ribosome assembly alongside factors such as ribosomal proteins (e.g., RPL5 and RPL11). Upon nucleolar stress—induced by insults like actinomycin D treatment or ribosomal protein depletion—NPM1 translocates to the nucleoplasm, where it complexes with to inhibit ubiquitination and degradation, thereby stabilizing and triggering its transcriptional activity. This translocation is a hallmark of nucleolar stress and is essential for activation, as nucleoplasm-restricted NPM1 mutants fail to induce accumulation. Additionally, NPM1 directly interacts with , a key regulator of ribosomal biogenesis, to control -driven proliferation; NPM1 binding attenuates excessive activity during unscheduled ribosome production, enforcing a checkpoint that prevents oncogenic transformation. The positions NPM1 at the interface of mitotic regulation, particularly through its interaction with the Aurora-B kinase pathway to ensure chromosomal fidelity. During , Aurora-B NPM1 at serine 125, promoting its redistribution and supporting duplication and spindle assembly. This is critical for mitotic progression, as inhibition of Aurora-B disrupts NPM1 localization and leads to defects in chromosome segregation. Protein-protein interaction analyses, such as those from the database, reveal that NPM1 engages over 150 high-confidence interactors, many enriched in and modules, underscoring its role in a broader that safeguards against . Feedback loops involving NPM1 further fine-tune apoptotic responses via the NPM1-- circuit. NPM1 directly binds in the , sequestering it and preventing MDM2 from ubiquitinating , which stabilizes p53 levels and promotes in response to genotoxic stress. This interaction forms a regulatory axis where NPM1 acts as a brake on MDM2 activity; disruption of NPM1-MDM2 binding, as seen with certain modulators, enhances p53-MDM2 association and accelerates p53 degradation, dampening apoptotic signaling. In UV-induced damage, NPM1's nucleoplasmic relocation amplifies this loop by further inhibiting MDM2-p53 interactions, linking nucleolar integrity to genome stability.

Pathological Roles

Somatic Mutations

Somatic mutations in the NPM1 gene are a hallmark of (AML), occurring primarily as heterozygous alterations that drive leukemogenesis through protein mislocalization. These mutations are detected in approximately 30% of adult de novo AML cases overall and in up to 50-60% of those with normal . The predominant somatic mutations are frameshift insertions in 12, accounting for over 95% of NPM1 alterations in AML. The most common variant, known as type A, involves a duplication of the TCTG sequence at 960-963, leading to a +4 bp shift that replaces the C-terminal 7 (including the nucleolar localization signal at tryptophans 288 and 290) with 11 novel residues and creates a new . This , representing 70-80% of NPM1-mutated AML cases, results in a protein designated NPM1c+. Less frequent 12 variants include type B (CATG insertion) and type D (CCTG insertion), each occurring in about 5-10% of cases. The molecular consequences of these exon 12 frameshifts profoundly alter NPM1 function. The C-terminal modification abolishes the nuclear localization signal (NLS), preventing nucleolar retention and causing aberrant cytoplasmic accumulation of NPM1c+, which is observed in nearly all leukemic blasts of affected patients. Despite retaining the N-terminal oligomerization domain, the mutant protein forms stable heteropentamers with wild-type NPM1, sequestering the latter into the and disrupting its normal nucleolar localization. This mislocalization impairs NPM1's chaperone and nucleolar functions, contributing to genomic instability and leukemic transformation. Other somatic NPM1 mutations are rare and include missense variants in the N-terminal oligomerization domain, which can destabilize pentamer formation and further compromise protein interactions, though they occur in less than 5% of NPM1-mutated AML. In contrast, NPM1 variants, distinct from somatic changes, have been associated with developmental disorders such as dysmorphism, congenital malformations, and neurodevelopmental delay due to defects in rRNA processing. NPM1 mutations frequently co-occur with other genetic alterations in AML, notably internal tandem duplications in FLT3 (FLT3-ITD), observed in approximately 40% of NPM1-mutated cases based on 2023-2024 cohort analyses. This co-occurrence enhances proliferative signaling but is mutually exclusive with certain other mutations like RUNX1 alterations.

Association with Acute Myeloid Leukemia

NPM1 mutations are a defining genetic abnormality in (AML), occurring in approximately 30% to 35% of adult cases overall and in 45% to 60% of those with cytogenetically normal karyotypes (CN-AML). These mutations establish NPM1-mutated AML as a distinct diagnostic entity in the 5th edition of the classification of hematopoietic neoplasms and the 2022 International Consensus , characterized by frameshift mutations typically in 12 leading to cytoplasmic localization of the NPM1 protein (NPM1c+). In terms of , NPM1-mutated AML without concurrent FLT3 internal tandem duplication (FLT3-ITD) is associated with a favorable outcome, with 5-year overall survival rates approaching 60% in intensively treated adults, though this benefit diminishes in older patients or those with high FLT3-ITD allelic ratios. The pathogenic mechanism involves NPM1c+ mislocalization to the , which disrupts normal nucleolar sequestration of the tumor suppressor ARF, thereby inhibiting and stabilizing ; additionally, NPM1c+ aberrantly activates HOX cluster genes, promoting leukemic self-renewal. Recent 2024 analyses have further linked NPM1 mutations to intra-patient heterogeneity in blast maturation, driving aberrant and differentiation blockade at primitive stages. Beyond AML, NPM1 mutations are rare in solid tumors, where they lack the specificity seen in myeloid neoplasms, and NPM1 overexpression has been implicated in the progression of myelodysplastic syndromes (MDS) to AML through enhanced proliferative signaling. Overexpression of NPM1 is also observed in various solid tumors, including , , and gastric cancers, where it promotes cell survival and proliferation. In hematological malignancies beyond AML, NPM1-ALK gene fusions occur in approximately 80% of anaplastic large cell lymphomas (ALCL), resulting in constitutive activation of ALK and driving lymphomagenesis. In pediatric AML, NPM1 mutations occur at a lower frequency of about 8% to 10% and confer a generally favorable , though outcomes vary with co-mutations and age.

Therapeutic Targeting and Prognosis

Monitoring of measurable residual disease (MRD) in NPM1-mutated (AML) primarily relies on reverse transcription quantitative (RT-qPCR) assays targeting NPM1 mutations, which achieve a sensitivity of 10^{-4} to 10^{-5} (0.01% to 0.001%). This method is predictive of relapse risk and overall survival, with persistent MRD post-induction associated with inferior outcomes. According to the 2025 European LeukemiaNet (ELN) MRD guidelines, RT-qPCR is recommended for NPM1-mutated AML to guide risk stratification after induction therapy, enabling decisions on consolidation strategies such as allogeneic (HSCT). Targeted therapies exploiting NPM1 mutations focus on disrupting aberrant localization and downstream pathways. Exportin-1 (XPO1) inhibitors, such as , promote nuclear relocalization of the mutant NPM1c protein by blocking its cytoplasmic export, leading to differentiation and reduced proliferation in NPM1-mutated AML cells. Prolonged XPO1 inhibition is required for optimal antileukemic effects, including downregulation of HOX/MEIS genes. For cases with co-occurring mutations, menin-MLL inhibitors like revumenib target the menin-MLL interaction critical for leukemogenesis in NPM1-mutated AML; phase II trials in relapsed/refractory NPM1-mutated AML have reported an overall response rate of approximately 47%, with 23% achieving complete remission (CR) or CR with partial hematologic recovery. Prognosis in NPM1-mutated AML is favorable when the mutation occurs without a co-existing FLT3 internal tandem duplication (FLT3-ITD), as defined by the ELN 2022 risk stratification, conferring intermediate to favorable with standard . High-risk subsets, such as those with high allelic ratio FLT3-ITD, benefit from allogeneic HSCT in first CR, which reduces relapse and improves long-term survival compared to alone. Emerging data from 2024 on venetoclax-based combinations, particularly with hypomethylating agents, have shown improved CR rates of around 80-85% in unfit patients with NPM1-mutated AML, enhancing accessibility for older or comorbid individuals.

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