Nucleophosmin and human cancer

Abstract

Nucleophosmin (NPM) is a nucleolar phosphoprotein that shuttles between the nucleus and cytoplasm during the cell cycle. NPM has several interacting partners and diverse cellular functions, including the processing of ribosomal RNA, centrosome duplication and the control of cellular processes to ensure genomic stability. Subcellular localization of NPM appears to be strongly correlated with NPM functions and cell proliferation. NPM is phosphorylated mainly at its central acidic domain by several upstream kinases, and its phosphorylation appears to be involved in regulating its functions in ribosome biogenesis and centrosome duplication. Recent studies suggest that NPM may act as a licensing factor to maintain proper centrosome duplication and that the Ran/CRM1 nucleocytoplasmic complex regulates local trafficking of NPM to centrosomes by interacting through its nuclear export sequence motif. Here, we provide a brief overview of NPM functions and its roles in human carcinogenesis, and discuss our recent findings related to the potential mechanisms underlying its regulation of centrosome duplication.

Fig. 1

A schematic representation of the human NPM gene. (A) NPM exists as at least three isoforms, variants 1, 2 and 3. The relative sizes and positions of exons are represented by the numbers 1 .12. The line (-) represents multiple alternative splicing events. Blue and yellow areas indicate coding sequences and untranslated regions, respectively. (B) Structure of the wild-type human NPM gene. The regular-spliced NPM gene has 11 exons encoding 294 amino acids. The N-terminal and C-terminal portions of NPM are essential for oligomer formation and nucleic acid binding activity, respectively. The central region of NPM is highly acidic. AD denotes the acidic domain and NAB, the nucleic acid domain. NPM that contains several known and potential phosphorylation sites by cdc2, CKII or N-II kinase, and plk1 are shown in red, green and light blue, respectively. The NES (yellow), NLS (green), and NoLS (red) motifs are highlighted and are conserved among four different species. Prefixes: h, human; m, mouse; r, rat; xl, Xenopus laevis. (C) The C-terminus of NPM is frequently mutated in AML. The positions of the two C-terminal tryptophan (W) residues are represented by red and the mutated residues are shown in pink. The added amino acid sequences common to all the mutated proteins are represented by the light blue box. (D) The NPM N-terminal portions are translocated to ALK, RAR or MLF in lymphoma and leukemia, and their sites are also indicated.

Fig. 2

NPM functions as a licensing factor for centrosome duplication and its transportation to the centrosome is regulated by the Ran/CRM1 complex. NPM associates specifically with unduplicated centrosomes, and dissociates from centrosomes following CDK2 kinase phosphorylation during late G1 phase. This event allows centrosome duplication to take place. During cell cycle progression from the S to the G2 phase, NPM is mainly located in the nucleolus where it acts as a regulator of ribosome biogenesis. When the nuclear membrane breaks down at the beginning of mitosis, NPM is relocalized to the centrosome, resulting in the prevention of centrosome reduplication. Newly divided cells contain a NPM-bound centrosome. During mitosis, NPM relocalization to the centrosomes occurs by interacting with the Ran/CRM1 complex through the NES motif. Ran, a small GTPase, can cycle between an active GTP and an inactive GDP-bound form by RCC1 and RanBP1, respectively. GTP-bound Ran localizes at the centrosome with AKAP and CRM1. Inhibition of CRM1 by LMB or HBx, and NES inactivation by phosophorylation at T95, or through mutation of the NPM NES motif of NPM, leads to dissociation from the centrosome and eventually allows centrosome amplication.

Fig. 3

Variable cellular localization of NPMs and its physiological roles. The cellular functions of NPMs are tightly regulated by multiple factors that determine the direction of NPM functions. Oligomerization may modulate the nucleic acid binding activity and chaperone activity of NPM during ribosome biogenesis, and hetero-oligomerization with isoform, NPM1.2, impairs nucleic acid binding activity. NPM phosphorylation by various upstream kinases is necessary to regulate its function in ribosome biogenesis, centrosome duplication and cell cycle progression. NPM can localize in several places and its local trafficking to the specific target sites leads to coordinated ribosome biogenesis, centrosome duplication and cell cycle progression. NPM functions as a pivotal regulator for controlling cell cycle progression, centrosome duplication, genomic instability, as well as carcinogenesis. Alteration of NPM function through mutation or translocation may contribute to oncogenesis.