Role of nucleophosmin in embryonic development and tumorigenesis

Abstract

Nucleophosmin (also known as NPM, B23, NO38) is a nucleolar protein directly implicated in cancer pathogenesis, as the NPM1 gene is found mutated and rearranged in a number of haematological disorders. Furthermore, the region of chromosome 5 to which NPM1 maps is deleted in a proportion of de novo human myelodysplastic syndromes (MDS), and loss of chromosome 5 is extremely frequent in therapy-related MDS. NPM is a multifunctional protein, and its role in oncogenesis is controversial as NPM has been attributed with both oncogenic and tumour suppressive functions. To study the function of Npm in vivo, we generated a hypomorphic Npm1 mutant series (Npm1+/- < Npm1(hy/hy) < Npm1-/-) in mouse. Here we report that Npm is essential for embryonic development and the maintenance of genomic stability. Npm1-/- and Npm1(hy/hy) mutants have aberrant organogenesis and die between embryonic day E11.5 and E16.5 owing to severe anaemia resulting from defects in primitive haematopoiesis. We show that Npm1 inactivation leads to unrestricted centrosome duplication and genomic instability. We demonstrate that Npm is haploinsufficient in the control of genetic stability and that Npm1 heterozygosity accelerates oncogenesis both in vitro and in vivo. Notably, Npm1+/- mice develop a haematological syndrome with features of human MDS. Our findings uncover an essential developmental role for Npm and implicate its functional loss in tumorigenesis and MDS pathogenesis.

Binding to nucleophosmin determines the localization of human and chicken ARF but not its impact on p53

“…These results are broadly consistent with previous reports, allowing for differences in the effectiveness of NPM knockdown (Kuo et al, 2004;Korgaonkar et al, 2005). In this regard, the most persuasive evidence for the role of NPM comes from studies on NPM-knockout mice Grisendi et al, 2005). At the cellular level, genetic ablation of NPM results in displacement of p19 ARF from the nucleolus accompanied by a dramatic loss in stability .…”

An Extensive Tumor Array Analysis Supports Tumor Suppressive Role for Nucleophosmin in Breast Cancer

“…24,46 More importantly, NPM haploinsufficiency in NPM ϩ/Ϫ mouse embryonic fibroblasts that mimic cancer cells harboring chromosomal rearrangements/deletions at the NPM1 locus show an immortal phenotype with noticeably high proliferation rates. 47 Furthermore, in the p53 Ϫ/Ϫ background, NPM ϩ/Ϫ mouse embryonic fibroblasts have higher proliferation rates than NPM ϩ/ϩ mouse embryonic fibroblasts, and they are more susceptible to transformation by activated oncogenes, indicating that loss of one Npm1 allele cooperates with oncogenes in transformation and tumorigenesis both in vitro and in vivo. 46 Npm1 ϩ/Ϫ mice show higher susceptibility for development of malignancies, especially of hematological and lymphoid origin, than their wild-type counterparts, indicating NPM as a haploinsufficient tumor suppressor.…”

B23 acts as a nucleolar stress sensor and promotes cell survival through its dynamic interaction with hnRNPU and hnRNPA1

“…This study, together with earlier reports from other group, indicates that B23 is a 'difficile molecule'. On one hand, B23 overexpression accounts for the drug resistance of tumor cells to ActD treatment, and on the other hand, lacking of B23 will induce tumorigenesis by impairing genome stability (Grisendi et al, 2005). New therapeutic agents that specifically targeting the B23-invovled pathways, for example 3 0 -UTR of bcl-xL mRNA that block B23-hnRNPU interaction, may provide the opportunity to achieve more effective and rational cancer therapy.…”