The NPM1 gene encodes for a protein involved in multiple functions. (A) The NPM1 gene contains 12 exons. NPM1 is translated from exons 1 to 9 and 11 to 12. The portion encoding isoform B23.2 contains exons 1 to 10. In the protein, the N-terminus is characterized by a nonpolar domain responsible for oligomerization and heterodimerization. Functional nuclear export signal (NES) motifs and a metal-binding (MB) domain are present in this region. The central portion of the protein contains 2 acidic stretches (Ac) that are important for binding to histones, and a bipartite nuclear localization signal (NLS); this region confers ribonuclease activity. The C-terminus of the protein shows ribonuclease activity and contains basic regions involved in nucleic-acid binding. The latter are followed by an aromatic stretch, unique to NPM isoform 1, which contains 2 tryptophan residues (288 and 290), which are required for nucleolar localization of the protein (NoLS). (B) NPM is a nucleolar phosphoprotein that shuttles between the nucleus and cytoplasm. Shuttling plays a fundamental role in ribosome biogenesis, since NPM transports preribosomal particles. In cytoplasm, NPM binds to the unduplicated centrosome and regulates its duplication during cell division. Furthermore, NPM interacts with p53 and its regulatory molecules (ARF, Hdm2/Mdm2) influencing the ARF-Hdm2/Mdm2-p53 oncosuppressive pathway.