NPM1

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NPM1
Protein NPM1 PDB 2p1b.png
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
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001252260
NM_001252261
NM_008722

RefSeq (protein)

NP_001239189
NP_001239190
NP_032748

Location (UCSC)Chr 5: 171.39 – 171.41 Mbn/a
PubMed search[2][3]
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.[4][5]

Function[]

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 ) 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 is phosphorylated.

Nucleophosmin has multiple functions:[6]

  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.[7] 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,[8] 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.[9]

Interactions[]

NPM1 has been shown to interact with

Nucleophosmin has multiple binding partners:[6]

  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. ^ a b c GRCh38: Ensembl release 89: ENSG00000181163 - Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ Liu QR, Chan PK (March 1993). "Characterization of seven processed pseudogenes of nucleophosmin/B23 in the human genome". DNA and Cell Biology. 12 (2): 149–56. doi:10.1089/dna.1993.12.149. PMID 8471164.
  5. ^ 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. Bibcode:1994Sci...263.1281M. doi:10.1126/science.8122112. PMID 8122112.
  6. ^ a b Lindström MS (2011). "NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling". Biochemistry Research International. 2011: 1–16. doi:10.1155/2011/195209. PMC 2989734. PMID 21152184.
  7. ^ 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" (PDF). Haematologica. 92 (4): 519–32. doi:10.3324/haematol.11007. hdl:2434/424144. PMID 17488663.
  8. ^ Meani N, Alcalay M (September 2009). "Role of nucleophosmin in acute myeloid leukemia". Expert Review of Anticancer Therapy. 9 (9): 1283–94. doi:10.1586/era.09.84. PMID 19761432. S2CID 7390794.
  9. ^ Loberg MA, Bell RK, Goodwin LO, Eudy E, Miles LA, SanMiguel JM, Young K, Bergstrom DE, Levine RL, Schneider RK, Trowbridge JJ (January 2019). "Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis". Leukemia. 33 (7): 1635–1649. doi:10.1038/s41375-018-0368-6. PMC 6609470. PMID 30692594.
  10. ^ 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". Proceedings of the National Academy of Sciences of the United States of America. 105 (43): 16584–9. Bibcode:2008PNAS..10516584L. doi:10.1073/pnas.0807668105. PMC 2569968. PMID 18931307.
  11. ^ a b 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". The Journal of Biological Chemistry. 279 (30): 30919–22. doi:10.1074/jbc.C400169200. PMID 15184379. S2CID 23001611.
  12. ^ Li YP, Busch RK, Valdez BC, Busch H (April 1996). "C23 interacts with B23, a putative nucleolar-localization-signal-binding protein". European Journal of Biochemistry. 237 (1): 153–8. doi:10.1111/j.1432-1033.1996.0153n.x. PMID 8620867.

Further reading[]

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