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
The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of sign ...
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
ribosome
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
s and may assist small basic proteins in their transport to the
nucleolus. Its regulation through
SUMOylation
In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (sometimes w ...
(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:
# Histone
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
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
Acute promyelocytic leukemia (APML, APL) is a subtype of acute myeloid leukemia (AML), a cancer of the white blood cells. In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by a ...
,
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
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with
*
AKT1,
*
BARD1,
[
* BRCA1,]
References
Further reading
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{{PDB Gallery, geneid=4869
Genes on human chromosome 5