Nucleophosmin Is Required for DNA Integrity and p19<sup>Arf</sup> Protein Stability

Colombo, Emanuela; Bonetti, Paola; Denchi, Eros Lazzerini; Martinelli, Paola; Zamponi, Raffaella; Marine, Jean–Christophe; Helin, Kristian; Falini, Brunangelo; Pelicci, Pier Giuseppe

doi:10.1128/mcb.25.20.8874-8886.2005

Cited by 203 publications

(226 citation statements)

References 44 publications

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“…These reciprocal antagonistic signals eliminate the cellular fail-safe mechanisms induced by oncogenes, namely Arf/p53 activation and senescence, unleashing the oncogenic potential of E1A and NPMc þ . Since NPM is required for Arf stability (Colombo et al, 2005), our data suggest two possibilities for the dominant-negative action of NPMc þ on Arf: NPMc þ delocalizes NPM to the cytoplasm, thus attenuating NPM's protective role on Arf (den Besten et al, 2005), or NPMc þ directly delocalizes Arf to the cytoplasm and destabilizes it (Colombo et al, 2006). Our data showed that the endogenous NPM was only partially delocalized by NPMc þ (Figure 1a), therefore supporting the second hypothesis.…”

Section: Discussionsupporting

confidence: 73%

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

et al. 2007

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Mutations leading to aberrant cytoplasmic localization of Nucleophosmin 1 (NPM1) have been recently identified as the most frequent genetic alteration in acute myelogenous leukemia. However, the oncogenic potential of this nucleophosmin mutant (NPMc +) has never been established, which casts doubt on its role in leukemogenesis. By performing classical transformation assays, we find that NPMc +, but not wild-type NPM, cooperates specifically with adenovirus E1A to transform primary mouse embryonic fibroblasts in soft agar. We demonstrate that NPMc + blocks the p19 Arf (Arf) induction elicited by E1A. Surprisingly, however, we find that NPMc + induces cellular senescence and that E1A is able to overcome this response. We propose a model whereby the NPMc + pro-senescence activity needs to be evaded for oncogenic transformation, even though NPMc + can concomitantly blunt the Arf/p53 pathway. These findings identify for the first time NPMc + as an oncogene and shed new unexpected light on its mechanism of action.

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Section: Discussionsupporting

confidence: 73%

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

et al. 2007

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“…NPM Ϫ/Ϫ primary fibroblasts (mouse embryonic fibroblasts) show centrosome amplification, polyploidy, activation of p53, growth arrest, and senescence. 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.…”

Section: Discussionmentioning

confidence: 99%

“…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. 29 Here we show that reduced NPM protein expression was associated with poor prognosis and that over-expression of NPM in the MDA-MB-231 breast cancer cells abrogated their growth in soft agar, supporting a tumor suppressive function for NPM in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

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

Karhemo

Rivinoja

Lundin

et al. 2011

The American Journal of Pathology

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Nucleophosmin (NPM) is a multifunctional protein involved in a complex network of interactions. The role of NPM in oncogenesis is controversial. The NPM gene (NPM1) is mutated or rearranged in a number of hematological disorders, but such changes have not been detected in solid cancers. However, experiments with cultured NPM-null cells and with mice carrying a single inactivated NPM allele indicate a tumor suppressor function for NPM. To resolve the role of NPM in solid cancers, we examined its expression and localization in histologically normal breast tissue and a large array of human breast carcinoma samples (n ‫؍‬ 1160), and also evaluated its association with clinicopathological variables and patient survival. The intensity and localization (nucleolar, nuclear, cytoplasmic) of NPM varied across clinical samples. No mutations explaining the differences were found, but the present findings indicate that expression levels of NPM affected its localization. Our study also revealed a novel granular staining pattern for NPM, which was an independent prognostic factor of poor prognosis. In addition, reduced levels of NPM protein were associated with poor prognosis. Nucleophosmin (NPM) is a ubiquitously expressed multifunctional nucleolar phosphoprotein. It localizes mainly to the nucleoli, but also shuttles in and out of the nucleolus, and between the nucleus and the cytoplasm. 1,2 NPM belongs to the nucleoplasmin family of nuclear chaperone proteins. It is involved in a complex network of interactions and has multiple functions. In addition to its chaperone activity, 3,4 NPM is involved in centrosome duplication, 5 ribosome biogenesis, 6,7 and environmental stress responses. 8,9 NPM also regulates the tumor suppressor proteins p53 10 -12 and p14 ARF . [13][14][15] Moreover, NPM protein is post-translationally modified by acetylation, 16 sumoylation, 17,18 ubiquitinylation, 19 and phosphorylation. 20 -23 NPM has been heavily implicated in cancer pathogenesis, but its actual role in oncogenesis is controversial. 24 NPM1 is mutated or rearranged in a number of hematological disorders, 25 and it is the most frequently mutated gene in acute myeloid leukemia. In addition, NPM protein is reported to be overexpressed in cancer cells, and it was originally proposed as a proto-oncogene. However, rapidly proliferating tumor cells could show elevated NPM levels, simply because NPM expression increases rapidly in early G1 phase during mitosis. 26 On the other hand, inactivation of NPM1 in the germline leads to embryonic lethality. 27,28 Moreover, experiments with cultured NPM-null cells 27,28 and mice carrying a single inactivated NPM allele indicate a tumor suppressor function for NPM. 27 NPM1

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“…In this regard, we have shown NSC348884 to induce apoptosis in several types of cancer cells even in the absence of other stressful events (Figure 4). A mouse NPM knockout experiment demonstrated that lack of NPM expression results in accumulation of DNA damage (Colombo et al, 2005). Apoptosis induced by NSC348884 may be involved in mediating increased DNA damage.…”

Section: Apoptosis Induction By Npm Inhibitor Nsc348884 W Qi Et Almentioning

confidence: 99%

NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells

et al. 2008

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Nucleophosmin (NPM), a multifunctional nucleolar phosphoprotein is dysregulated in human malignancies leading to anti-apoptosis and inhibition of differentiation.We evaluated the precise three-dimensional structure of NPM based on the highly conserved structure of Xenopus NO38 and its requirement to form dimers and pentamers via its N-terminal domain (residues, 1-107). We hypothesized that a small molecular inhibitor (SMI) that could disrupt the formation of dimers would inhibit aberrant NPM function(s) in cancer cells. Molecular modeling, pharmacophore design, in silico screening and interactive docking identified NSC348884 as a putative NPM SMI that disrupts a defined hydrophobic pocket required for oligomerization. NSC348884 inhibited cell proliferation at an IC 50 of 1.7-4.0 lM in distinct cancer cell lines and disrupted NPM oligomer formation by native polyacrylamide gel electrophoresis assay. Treatment of several different cancer cell types with NSC348884 upregulated p53 (increased Ser15 phosphorylation) and induced apoptosis in a dose-dependent manner that correlated with apoptotic markers: H2AX phosphorylation, poly(ADPribose) polymerase cleavage and Annexin V labeling. Further, NSC348884 synergized doxorubicin cytotoxicity on cancer cell viability. The data together show that NSC348884 is an SMI of NPM oligomer formation, upregulates p53, induces apoptosis and synergizes with chemotherapy. Hence, an SMI to NPM may be a useful approach to anticancer therapy.

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Nucleophosmin Is Required for DNA Integrity and p19^Arf Protein Stability

Cited by 203 publications

References 44 publications

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

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

NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells

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Nucleophosmin Is Required for DNA Integrity and p19Arf Protein Stability

Cited by 203 publications

References 44 publications

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

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

NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells

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Nucleophosmin Is Required for DNA Integrity and p19^Arf Protein Stability