Nucleophosmin and cancer

Abstract

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.