Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases

Colombo, Emanuela; Alcalay, Myriam; Pelicci, P. G.

doi:10.1038/onc.2010.646

Cited by 193 publications

(200 citation statements)

References 169 publications

(205 reference statements)

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“…uS3) has been reported to act as an apurinic/apyrimidinic endonuclease in both nuclear and mitochondrial base excision repair (Kim et al 2013), while nucleostemin/GNL3 has been implicated in the recruitment of RAD51 to stalled replication forks Meng et al 2013), and Nol12 has D r a f t 5 been identified as an important protective factor against oxidative DNA damage (Scott et al 2016). Most strikingly, two proteins -nucleophosmin (NPM1) and nucleolin (NCL) -are required for optimal activity of multiple independent DNA repair pathways, and their dysregulation has been reported in numerous cancers, in particular leukemias and other myeloproliferative disorders (Berger et al 2015;Colombo et al 2011;Federici et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Scott

Oeffinger

2016

Biochem. Cell Biol.

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The nucleolus represents a highly multifunctional intranuclear organelle in which, in addition to the canonical ribosome assembly, numerous processes such as transcription, DNA repair and replication, the cell cycle and apoptosis are coordinated. The nucleolus is further a key hub in the sensing of cellular stress and undergoes major structural and compositional changes in response to cellular perturbations.Numerous nucleolar proteins have been identified that, upon nucleolar stress sensing, deploy additional, non-ribosomal roles in the regulation of varied cell processes including cell cycle arrest, arrest of DNA replication, induction of DNA repair, and apoptosis, among others. The highly abundant proteins nucleophosmin (NPM1) and nucleolin (NCL) are two such factors that transit to the nucleoplasm in response to stress, and participate directly in the repair of numerous different DNA damages. This review discusses the contributions made by NCL and/or NPM1 to the different DNA repair pathways employed by mammalian cells to repair DNA insults, and examines the implications of such activities for the regulation, pathogenesis and therapeutic targeting of NPM1 and NCL.

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Section: Introductionmentioning

confidence: 99%

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Scott

Oeffinger

2016

Biochem. Cell Biol.

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“…Certain nucleolar proteins such as NPM1 has dual roles in the nucleolus and nucleoplasm; its abnormal distribution after nucleolar perturbation may also affect the regulation of nucleoplasmic genes. 29 Knockdown of the NoRC nucleolar repressor subunit TIP5 has recently been shown to promote transformation of NIH3T3 cells. 30 Our data in this report suggests that nucleolar silencing may have an important role in maintaining cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

Nucleolar repression facilitates initiation and maintenance of senescence

Yang

Song

Soliman³

et al. 2015

Cell Cycle

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Tumor cells with defective apoptosis pathways often respond to chemotherapy by entering irreversible cell cycle arrest with features of senescence. However, rare cells can bypass entry to senescence, or re-enter cell cycle from a senescent state. Deficiency in senescence induction and maintenance may contribute to treatment resistance and early relapse after therapy. Senescence involves epigenetic silencing of cell cycle genes and reduced rRNA transcription. We found that senescence-inducing treatments such as DNA damage and RNA polymerase I inhibition stimulate the binding between the nucleolar protein NML (nucleomethylin) and SirT1. The NML complex promotes rDNA heterochromatin formation and represses rRNA transcription. Depletion of NML reduced the levels of H3K9Me3 and H3K27Me3 heterochromatin markers on rDNA and E2F1 target promoters in senescent cells, increased rRNA transcription, and increased the frequency of cell cycle re-entry. Depletion of the nucleolar transcription repressor factor TIP5 also promoted escape from senescence. Furthermore, tumor tissue staining showed that breast tumors without detectable nucleolar NML expression had poor survival. The results suggest that efficient regulation of nucleolar rDNA transcription facilitates the maintenance of irreversible cell cycle arrest in senescent cells. Deficiency in nucleolar transcription repression may accelerate tumor relapse after chemotherapy.

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“…10,15,16,23,24 Here, we focus on the C-terminal domain of the protein. We describe its structure, interactions, known physiological functions, and how they are modified in the NPM1 leukemic mutants.…”

Section: Nucleophosmin and Cancermentioning

confidence: 99%

“…6 In the last years, however, the number of cellular processes to which NPM1 participates, as well as the number of NPM1 cellular interactors, has grown exponentially and the protein is now thought to play a role also in chromatin remodeling, 7,8 centrosome duplication, 9 DNA replication, recombination, transcription, and repair as well as in the control of cell cycle progression and survival in response to a variety of stress stimuli. 10 NPM1 belongs to the NucleoPhosMin/NucleoPlasMin family of proteins, whose members are found throughout the animal kingdom, but not in yeast and bacteria. They can be further classified into four groups, based on sequence similarities: NPM1 (nucleophosmin), NPM2 (nucleoplasmin), NPM3, and NPM-like invertebrate proteins.…”

Section: Introductionmentioning

confidence: 99%

“…14 The N-terminal domain has also been reported to mediate NPM1 interactions with a plethora of other proteins, including p53, p14arf, Fbw7c, APE-1, ribosomal proteins RPL5, RPS9, RPL23, HIV proteins REV and TAT, and many others. 10,15,16 Through these interactions, none of which has been structurally characterized, NPM1 functions extend considerably beyond its role as a histone chaperone. Many of these proteins show nucleolar localization and it has been proposed that NPM1 favors their correct cellular localization, trafficking, stability, and activity, thus behaving as a nucleolar hub protein.…”

Section: Introductionmentioning

confidence: 99%

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Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization

Federici

Falini

2013

Protein Science

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Nucleophosmin (NPM1) is an abundant, ubiquitously expressed protein mainly localized at nucleoli but continuously shuttling between nucleus and cytoplasm. NPM1 plays a role in several cellular functions, including ribosome biogenesis and export, centrosome duplication, chromatin remodeling, DNA repair, and response to stress stimuli. Much of the interest in this protein arises from its relevance in human malignancies. NPM1 is frequently overexpressed in solid tumors and is the target of several chromosomal translocations in hematologic neoplasms. Notably, NPM1 has been characterized as the most frequently mutated gene in acute myeloid leukemia (AML). Mutations alter the C-terminal DNAbinding domain of the protein and result in its aberrant nuclear export and stable cytosolic localization. In this review, we focus on the leukemia-associated NPM1 C-terminal domain and describe its structure, function, and the effect exerted by leukemic mutations. Finally, we discuss the possibility to target NPM1 for the treatment of cancer and, in particular, of AML patients with mutated NPM1 gene.

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Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases

Cited by 193 publications

References 169 publications

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Nucleolar repression facilitates initiation and maintenance of senescence

Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization

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