Biology:NPM1

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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

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 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 is phosphorylated.

Nucleophosmin has multiple functions:

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

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. 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, 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.

Interactions

NPM1 has been shown to interact with

• AKT1,
• BARD1,
• BRCA1, and
• nucleolin.

Nucleophosmin has multiple binding partners:

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

Further reading

• "Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases". The Journal of Cell Biology 183 (4): 589–95. November 2008. doi:10.1083/jcb.200807185. PMID 19015314. 
• "The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing". EMBO Reports 9 (3): 273–9. March 2008. doi:10.1038/embor.2008.3. PMID 18259216. 
• "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Research 15 (11–12): 923–34. 2006. doi:10.1038/sj.cr.7290370. PMID 16354571. 
• "DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer". Journal of Molecular Histology 37 (5–7): 239–51. September 2006. doi:10.1007/s10735-006-9040-y. PMID 16855788. 
• "Nucleophosmin gene mutations in acute myeloid leukemia". Archives of Pathology & Laboratory Medicine 130 (11): 1687–92. November 2006. doi:10.5858/2006-130-1687-NGMIAM. PMID 17076533. 
• "Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias". Haematologica 92 (4): 519–32. April 2007. doi:10.3324/haematol.11007. PMID 17488663. https://air.unimi.it/bitstream/2434/424144/3/Bolli_Haematologica_Translocations_2007.pdf. 
• "Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element". Molecular and Cellular Biology 11 (5): 2567–75. May 1991. doi:10.1128/MCB.11.5.2567. PMID 2017166. 
• "Functional domains of the HIV-1 rev gene required for trans-regulation and subcellular localization". Virology 176 (1): 39–47. May 1990. doi:10.1016/0042-6822(90)90228-J. PMID 2109912. 
• "Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function". Journal of Virology 64 (2): 881–5. February 1990. doi:10.1128/JVI.64.2.881-885.1990. PMID 2404140. 
• "Amino acid sequence of a specific antigenic peptide of protein B23". The Journal of Biological Chemistry 261 (30): 14335–41. October 1986. doi:10.1016/S0021-9258(18)67023-1. PMID 2429957. 
• "Isolation and characterization of a molecular cDNA clone of a human mRNA from interferon-treated cells encoding nucleolar protein B23, numatrin". Biochemical and Biophysical Research Communications 164 (1): 176–84. October 1989. doi:10.1016/0006-291X(89)91699-9. PMID 2478125. 
• "Nucleotide sequence of a cDNA clone representing a third allele of human protein B23". Nucleic Acids Research 17 (23): 10112. December 1989. PMID 2602120. 
• "Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth". Biochemistry 28 (3): 1033–9. February 1989. doi:10.1021/bi00429a017. PMID 2713355. 
• "The nucleotide sequence of a human cDNA encoding the highly conserved nucleolar phosphoprotein B23". Biochemical and Biophysical Research Communications 163 (1): 72–8. August 1989. doi:10.1016/0006-291X(89)92100-1. PMID 2775293. 
• "Amino acid sequence of protein B23 phosphorylation site". The Journal of Biological Chemistry 261 (4): 1868–72. February 1986. doi:10.1016/S0021-9258(18)67023-1. PMID 3944116. 
• "In vitro and ex vivo expression of nucleolar proteins B23 and p120 in benign and malignant epithelial lesions of the prostate". Modern Pathology 8 (3): 226–31. April 1995. PMID 7542384. 
• "The roles of nucleolar structure and function in the subcellular location of the HIV-1 Rev protein". Journal of Cell Science 108 ( Pt 8) (8): 2811–23. August 1995. doi:10.1242/jcs.108.8.2811. PMID 7593322. 
• "The cytotoxicity of human immunodeficiency virus type 1 Rev: implications for its interaction with the nucleolar protein B23". Experimental Cell Research 219 (1): 93–101. July 1995. doi:10.1006/excr.1995.1209. PMID 7628555. 
• "Interaction of nucleolar protein B23 with peptides related to nuclear localization signals". Biochemistry 34 (25): 8037–42. June 1995. doi:10.1021/bi00025a009. PMID 7794916. 
• "Construction of a human full-length cDNA bank". Gene 150 (2): 243–50. December 1994. doi:10.1016/0378-1119(94)90433-2. PMID 7821789. 
• "Spatial association of HIV-1 tat protein and the nucleolar transport protein B23 in stably transfected Jurkat T-cells". Archives of Virology 139 (1–2): 133–54. 1995. doi:10.1007/BF01309460. PMID 7826206. 
• "Identification of the nuclear and nucleolar localization signals of the protein p120. Interaction with translocation protein B23". The Journal of Biological Chemistry 269 (38): 23776–83. September 1994. doi:10.1016/S0021-9258(17)31583-1. PMID 8089149.