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  • Review Article
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Nucleophosmin and cancer

Nature Reviews Cancer volume 6, pages 493–505 (2006)Cite this article

Key Points

  • Nucleophosmin (NPM, also known as B23) is a ubiquitously expressed nucleolar phosphoprotein that constantly shuttles between the nucleus and cytoplasm. NPM contains distinct functional domains through which it has many functions in the cell.

  • NPM is involved in cellular activities related to both proliferation and growth-suppression pathways. It participates in the process of ribosome biogenesis, and it controls genetic stability through the regulation of centrosome duplication. As a result, NPM overexpression correlates with uncontrolled cell growth and cellular transformation, whereas the disruption of NPM expression can cause genomic instability and centrosome amplification, which increases the risk of cellular transformation.

  • NPM is involved in the apoptotic response to stress and oncogenic stimuli (such as DNA damage and hypoxia), and it can modulate the activity and stability of crucial tumour-suppressor proteins such as p53.

  • Loss of NPM function leads to the destabilization and functional impairment of the ARF tumour-suppressor pathways, as NPM functions as a positive regulator of ARF protein stability.

  • NPM is implicated in human tumorigenesis. NPM is frequently overexpressed in solid tumours of a diverse histological origin, and genetic alterations that involve NPM1 occur frequently in haematopoietic tumours, such as chromosomal translocations in both lymphoid and myeloid disorders, and mutations in acute myeloid leukaemia (AML).

  • In tumour cells where NPM1 has been altered, NPM function can potentially be impaired both by the presence of antagonizing mutated products hetero-dimerizing with the wild-type protein, and by the reduction in the dosage of the gene to a single functional allele.

  • Depending on its expression levels and gene dosage, NPM seems to function as either an oncogene or a tumour suppressor. Either partial functional loss or aberrant overexpression could lead to neoplastic transformation through distinct mechanisms.

Abstract

NPM1 is a crucial gene to consider in the context of the genetics and biology of cancer. NPM1 is frequently overexpressed, mutated, rearranged and deleted in human cancer. Traditionally regarded as a tumour marker and a putative proto-oncogene, it has now also been attributed with tumour-suppressor functions. Therefore, NPM can contribute to oncogenesis through many mechanisms. The aim of this review is to analyse the role of NPM in cancer, and examine how deregulated NPM activity (either gain or loss of function) can contribute to tumorigenesis.

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Figure 1: Schematic representation of NPM1 gene translocations and mutations in leukaemia and lymphoma.
Figure 2: How NPM1 gene alteration in human cancer can contribute to tumorigenesis.
Figure 3: NPM overexpression in tumour cells leads to increased proliferation and inhibition of apoptosis.
Figure 4: NPM and ARF regulate cellular growth and proliferation through the control of each others stability and/or activity.
Figure 5: Hypothetical model of NPM involvement in the control of centrosome duplication and mitosis.

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Acknowledgements

We are grateful to C. Sherr and J. Weber for constructive comments, and to J. Clohessy, R. Bernardi, L. DiSantis and the other members of the P.P.P. laboratory for discussion and critical reading of the manuscript. We apologize to those whose papers could not be cited owing to space limitations. The work of P.P.P. and B.F. is supported by the US National Cancer Institute and the Italian Association for Cancer Research (AIRC), respectively.

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  1. Department of Pathology, Cancer Biology & Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Silvia Grisendi & Pier Paolo Pandolfi

  2. Institute of Haematology, Policlinico Monteluce, Perugia, Italy

    Cristina Mecucci & Brunangelo Falini

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  1. Silvia Grisendi
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Oncomine

Glossary

Chromosomal translocations

A translocation is the transfer of genetic material from one chromosome to another. Translocations between non-homologous chromosomes can bring two previously unlinked segments of the genome together, which in some cases can result in disease by inducing the inappropriate expression of a protein or the synthesis of a new fusion protein.

Nucleosome

The nucleosome is the fundamental repeating subunit of eukaryotic DNA. It is composed of DNA and histone proteins, the central core particles of the nucleosome. Nucleosomes are involved in a number of processes, including the compaction of DNA and transcriptional control.

SnoRNPs

Small nucleolar ribonucleoproteins are complexes of small nucleolar RNAs and proteins identified in eukaryotic cells. They function in pre-ribosomal RNA processing reactions and guide methylation and pseudouridylation of ribosomal RNA, spliceosomal small nuclear RNAs, and possibly other cellular RNAs.

Internal transcribed spacer

The ITS is a sequence in the precursor ribosomal RNA (rRNA) molecule, coded by ribosomal DNA. It lies between precursor ribosomal subunits, and is removed when the rRNA precursor is processed into a ribosome. Eukaryotic organisms have two internal transcribed spacers: ITS1 is located between the 18S gene and the 5.8S gene, while ITS2 is located between the 5.8S and the 28S gene.

Sumoylation

A post-translational modification that consists of covalent attachment of the small ubiquitin-like molecule, SUMO1 (also known as sentrin, PIC1). Sumoylation can change the ability of the modified protein to interact with other proteins and can interfere with its proteasomal degradation.

Genomic instability

Genomic instability indicates an increased tendency of the genome to acquire mutations when various processes involved in maintaining and replicating the genome are dysfunctional.

Centrosome

The centrosome is the main microtubule-organizing centre (MTOC) of the animal cell. It is composed of two orthogonally arranged centrioles surrounded by an amorphous mass of pericentriolar material. The centrosome duplicates before cell division, and each daughter MTOC functions as one pole of the mitotic-spindle apparatus.

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Grisendi, S., Mecucci, C., Falini, B. et al. Nucleophosmin and cancer. Nat Rev Cancer 6, 493–505 (2006). https://doi.org/10.1038/nrc1885

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