Nucleophosmin

Nucleophosmin is a protein that in humans is encoded by the NPM1 gene.

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Background


The multifunctional protein Nucleophosmin (NPM), also known as B23, N038, NPM1/B23.1 or numatrin, is ubiquitously expressed in mammals, birds and flies but could not be identified in bacteria or yeast. The NPM1 protein contains several functional domains, including an N-terminal region for oligomerization, molecular chaperone, acidic domains for histone binding and a C-terminal region for DNA/RNA binding. The N-terminus consists of 8 beta sheets forming a beta barrel while 2 highly acidic histone binding sites and a DNA/RNA binding region dominate the C-terminus. Structural analysis revealed that 5 monomers form a pentamer and that 2 pentamers stack on top of each other to form a decamer with overall dimensions of approximately 55x55x88A.

NPM migrates between the nucleus and the cytoplasm, depending on intracellular GTP and ATP levels. When the de novo synthesis of GTP is blocked and a constant depletion of GTP is registered, NPM-1 translocation takes place. Conversely, when ATP levels are depleted, NPM translocation is blocked and newly synthesized ribosomal RNA accumulates in nuclei and is not transported to the cytoplasm. Functions described for NPM include:

1. Protein assembly of pre-ribosomal particles, implicating its role in ribosome biogenesis.

2. Transport and molecular chaperoning, preventing protein aggregation, protecting enzymes during thermal denaturation and facilitating renaturation of chemically denatured proteins.

3. Binding of nucleic acids and helix-destabilizing function, for both DNA and RNA and physical interaction with maturating preribosomal ribonucleoproteins particles as well as nuclear localization signal binding. It is believed that NPM-1 even participates in DNA synthesis.

4. Ribonuclease activity, binding to nuclear localization signals and stress-response RNA-binding protein.

5. Pre mRNA processing.

6. Chromatin remodeling and assembly.

7. Relief of transcriptional repression by YY1, binding to HIV Type 1 Rev protein and p120 protein.

8. Control of centrosome duplication, and a necessary role in nucleolar disassembly.

9. Major gene product required for stem cell development, regulation of differentiation, cell cycle progression, and stress response in hematopoietic stem/progenitor cells.

The knockout of NPM in mice is embryonically lethal between day E11.5 and E16.5 indicating that NPM regulates essential processes. Indeed it could be shown that NPM is a multifunctional protein, involved in a wide range of actions. The schematic structure of NPM shows that it can bind to histones, acting as a histone chaperone, as well as to RNA and DNA. Next to its reported function in ribosome biogenesis NPM translocates from the nucleolus to the nucleoplasm upon DNA damage to bind damaged chromatin. Moreover NPM is crucial for the structural integrity of the nucleoli by interacting with the nucleolar proteins nucleolin and fibrillarin. Interestingly NPM was reported to localize to kinetochores where it associates with the centromere protein CENPA and is involved in correct kinetochore-microtubule interactions.

Several lines of evidence point to a role for NPM in human tumorigenesis. It could be shown that NPM promotes p53 stability by directly inhibiting the p53 ubiquitin ligase MDM2 and by stabilizing its inhibitor ARF. Therefore it is not surprising that NPM is frequently overexpressed, mutated and rearranged in human tumors. In particular NPM1 is altered in about one-third of acute myeloid leukemia patients, making it the most frequently altered gene in hematopoietic cancers.

References:

Marxer, M. (2012). New insights into the physiological functions and anti-cancer drug potential of aurora kinases (Doctoral dissertation).

Marquez-Lona, E. M. (2009). Elucidating the role of nucleolus in neuronal cell death pathways: Assessing the neuroprotective role of Nucleophosmin protein (NPM). University of California, Irvine.