Difference between revisions of "NPM1"
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==Gene Overview== | ==Gene Overview== | ||
| − | * ''NPM1' encodes for nucleophosmin and belongs to the nucleophosmin/nucleoplasmin family of proteins [1]. The protein shuttles between the nucleolus, nucleus and cytoplasm, though it primarily stays in the nucleolus; in normal conditions, nuclear import of ''NPM1'' predominates over export, and ''NPM1'' is predominantly functionally active in the nucleolus. In the maintenance of genomic stability, ''NPM1'' binds unduplicated centrosomes in the cytoplasm to prevent duplication, and dissociates to allow duplication; in this way, ''NPM1'' acts as a licensing system for centrosome duplication by facilitating coordination with DNA replication and restricting centrosome duplication to once per cell cycle [2]. The N-terminal domain contains two nuclear export signal motifs. The central region contains two acidic regions spanning a bipartite nuclear localization signal. The C-terminal domain contains both the nuclear localization signal and the nucleolar localization signal [3,4]. See Figure 1 in [4]. | + | * ''NPM1'' encodes for nucleophosmin and belongs to the nucleophosmin/nucleoplasmin family of proteins [1]. The protein shuttles between the nucleolus, nucleus and cytoplasm, though it primarily stays in the nucleolus; in normal conditions, nuclear import of ''NPM1'' predominates over export, and ''NPM1'' is predominantly functionally active in the nucleolus. In the maintenance of genomic stability, ''NPM1'' binds unduplicated centrosomes in the cytoplasm to prevent duplication, and dissociates to allow duplication; in this way, ''NPM1'' acts as a licensing system for centrosome duplication by facilitating coordination with DNA replication and restricting centrosome duplication to once per cell cycle [2]. The N-terminal domain contains two nuclear export signal motifs. The central region contains two acidic regions spanning a bipartite nuclear localization signal. The C-terminal domain contains both the nuclear localization signal and the nucleolar localization signal [3,4]. See Figure 1 in [4]. |
* In ribosome biogenesis, ''NPM1'' facilitates the export of pre-ribosomal proteins from the nucleus for incorporation into ribosomal subunits in the cytoplasms; as a chaperone, it coordinates the assembly of the large number of proteins required for ribosome biogenesis [3,4]. NPM1 also has histone chaperone function [4]. | * In ribosome biogenesis, ''NPM1'' facilitates the export of pre-ribosomal proteins from the nucleus for incorporation into ribosomal subunits in the cytoplasms; as a chaperone, it coordinates the assembly of the large number of proteins required for ribosome biogenesis [3,4]. NPM1 also has histone chaperone function [4]. | ||
Revision as of 11:50, 18 July 2018
Primary Author(s)*
Dr Kay Weng Choy MBBS, BMedSci, FAACB, Monash Health
Synonyms
Nucleophosmin 1, Nucleolar Phosphoprotein B23, Nucleolar Protein NO38, Numatri
Genomic Location
Cytoband: 5q35.1
Genomic Coordinates:
Put your text here
chr5:170,814,120-170,838,141 (GRCh37/hg19)
chr5:171,387,116-171,411,137 (GRCh38/hg38)
Cancer Category/Type
Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms
Acute Myeloid Leukemia (AML) with Mutated NPM1
Gene Overview
- NPM1 encodes for nucleophosmin and belongs to the nucleophosmin/nucleoplasmin family of proteins [1]. The protein shuttles between the nucleolus, nucleus and cytoplasm, though it primarily stays in the nucleolus; in normal conditions, nuclear import of NPM1 predominates over export, and NPM1 is predominantly functionally active in the nucleolus. In the maintenance of genomic stability, NPM1 binds unduplicated centrosomes in the cytoplasm to prevent duplication, and dissociates to allow duplication; in this way, NPM1 acts as a licensing system for centrosome duplication by facilitating coordination with DNA replication and restricting centrosome duplication to once per cell cycle [2]. The N-terminal domain contains two nuclear export signal motifs. The central region contains two acidic regions spanning a bipartite nuclear localization signal. The C-terminal domain contains both the nuclear localization signal and the nucleolar localization signal [3,4]. See Figure 1 in [4].
- In ribosome biogenesis, NPM1 facilitates the export of pre-ribosomal proteins from the nucleus for incorporation into ribosomal subunits in the cytoplasms; as a chaperone, it coordinates the assembly of the large number of proteins required for ribosome biogenesis [3,4]. NPM1 also has histone chaperone function [4].
- NPM1 has a crucial role in modulating stress response and growth suppression by stabilizing p53 in the nucleus, as well as inhibiting MDM2 (mouse double minute 2 homolog) (a p53 E3-ubiquitin ligase that causes inactivation of p53), ultimately contributing to growth arrest [5,6]. NPM1 prevents degradation of Arf (Alternate reading frame protein). As a tumor suppressor, Arf suppresses cell growth by disrupting ribosomal RNA precursor processing and suppressing ribosome biogenesis [7]; Arf also localizes MDM2 to the nucleolus and therefore inhibits MDM2, consequently relieving p53 inhibition. [8]. NPM1 controls the transcriptional activity of Myc at target gene promoters and influences Myc suppression by facilitating degradation of Myc [9]; NPM1 is required to localize and stabilize Fbw7γ (an F-box protein component to the E3 ubiquitin ligase complex) which promotes Myc degradation. See Figure 2 in [4].
- In the cytoplasm, NPM1 inhibits the activated forms of caspase-6 and -8 and reduces caspase-induced apoptosis/cell death [10].
Common Alteration Types
Put your text here and/or fill in the table with an X where applicable
| Copy Number Loss | Copy Number Gain | LOH | Loss-of-Function Mutation | Gain-of-Function Mutation | Translocation/Fusion |
|---|---|---|---|---|---|
| EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X |
Internal Pages
Acute Myeloid Leukemia (AML) with Mutated NPM1
External Links
NPM1 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information
NPM1 by COSMIC - sequence information, expression, catalogue of mutations
NPM1 by CIViC - general knowledge and evidence-based variant specific information
NPM1 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs
NPM1 by Cancer Genetics Web - gene, pathway, publication information matched to cancer type
NPM1 by OncoKB - mutational landscape, mutation effect, variant classification
NPM1 by My Cancer Genome - brief gene overview
NPM1 by UniProt - protein and molecular structure and function
NPM1 by Pfam - gene and protein structure and function information
NPM1 by GeneCards - general gene information and summaries
References
1. Federici L, Falini B, (2013). Nucleophosmin mutations in acute myeloid leukemia: a tale of protein unfolding and mislocalization. Protein Sci 22(5):545-556. PMID 23436734.
2. Okuda M, et al., (2000). Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103(1):127-140. PMID11051553.
3. Yu Y, et al., (2006). Nucleophosmin is essential for ribosomal protein L5 nuclear export. Mol Cell Biol 26(10): 3798-3809. PMID 16648475.
4. Heath EM, et al., (2017). Biological and clinical consequences of NPM1 mutations in AML. Leukemia 31(4):798-807. PMID 28111462.
5. Colombo E, et al., (2002). Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol 4(7):529-533. PMID 12080348.
6. Kurki S, et al., (2004). Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 5(5):465-475. PMID 15144954.
7. Bertwistle D, et al., (2004). Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. Mol Cell Biol 24(3):985-996. PMID 14729947.
8. Weber JD, et al., (1999). Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1(1):20-26. PMID 10559859.
9. Li Z, et al., (2008). Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation. Proc Natl Acad Sci USA 105(48):18794-18799. PMID 19033198.
10. Leong SM, et al., (2010). Mutant nucleophosmin deregulates cell death and myeloid differentiation through excessive caspase-6 and -8 inhibition. Blood 116(17):3286-3296. PMID 20606168.
11. Falini B, et al., (2006). Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. Blood 108(6):1999-2005. PMID 16720834.
12. Colombo E, et al., (2006). Delocalization and destabilization of the Arf tumor suppressor by the leukemia associated NPM mutant. Cancer Res 66(6):3044-3050. PMID 16540653.
13. Sportoletti P, et al., (2008). Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood 111(7):3859-3862. PMID 18212245.
14. Falini B, et al., (2005). Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352(3):254-266. PMID 15659725.
15. Döhner K, et al., (2005). Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106(12):3740-3746. PMID 16051734.
16. Ivey A, et al., (2016). Assessment of minimal residual disease in standard-risk AML. N Engl J Med 374(5):422-433. PMID 26789727.
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.