Nucleophosmin Serves as a Rate-Limiting Nuclear Export Chaperone for the Mammalian Ribosome

Maggi, Leonard B.; Kuchenruether, Michael; Dadey, David; Schwope, Rachel M.; Grisendi, Silvia; Townsend, R. Reid; Pandolfi, Pier Paolo; Weber, Jason D.

doi:10.1128/mcb.01548-07

Cited by 189 publications

(195 citation statements)

References 57 publications

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“…Interestingly, B23 has been shown to directly interact with L5 and play an essential role in its nuclear export (23). Interaction of these 2 proteins in a more general context was reported recently, when B23 was implicated in directing the nuclear export of both 40S and 60S ribosomal subunit proteins (42). L5 has also been reported to inhibit MDM2-mediated p53 ubiquitination and degradation, by inhibiting the E3 ubiquitin ligase activity of MDM2 (25,43,44).…”

Section: Discussionmentioning

confidence: 99%

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

Feldman

Roniger

Bar-Sinai

et al. 2012

Molecular Cancer Research

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Mouse mammary tumor virus (MMTV) is associated primarily with mammary carcinomas and lymphomas. The signal peptide of the MMTV envelope precursor is uniquely targeted to nucleoli of cells that harbor the virus, where it can function as a nuclear export factor for intron-containing transcripts. Antibodies to this signal peptide, which we refer to as p14, were previously shown to label nucleoli in a subset of human breast cancers. To look for additional cellular functions of p14, different mutants were ectopically expressed in the MCF-7 human breast cancer cell line. This approach identified motifs responsible for its nucleolar targeting, nucleocytoplasmic shuttling, target protein (B23, nucleophosmin) binding, and phosphorylation at serine 18 and 65 both in situ and in vitro. To test the role of these phosphorylation sites, we carried out in vivo tumorigenesis studies in severe combined immunodeficient mice. The findings show that the p14-Ser65Ala mutation is associated with impaired tumorigenicity, whereas the p14-Ser18Ala mutation is associated with enhanced tumorigenicity. Microarray analysis suggests that phosphorylation at serine 18 or at serine 65 is associated with transcriptional regulation of the L5 nucleolar ribosomal protein (a p14 target) and the Erb-B signal transduction pathway. Taken together, these results show that the phosphorylation status of p14 determines whether it functions as a pro-oncogenic or antioncogenic modulator.

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Section: Discussionmentioning

confidence: 99%

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

Feldman

Roniger

Bar-Sinai

et al. 2012

Molecular Cancer Research

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“…Secondly, NPM1 was found to associate with pre-rRNA within the nucleolus and mediate endonucleolytic cleavage within the Internal Transcribed Spacer 2 (ITS2), thereby separating the 28S and 5.8S rRNAs (Savkur and Olson 1998). Thirdly, NPM1 is able to bind to assembled 40S and 60S ribosomal subunits and promote their nuclear export via the CRM1 pathway, acting as a nucleocytoplasmic chaperone (Maggi et al 2008;Yu et al 2006). In addition to these roles, NPM1 possesses numerous nonribosomal functions.…”

Section: Nucleophosmin and Nucleolin: Two Multifunctional Nucleolar Pmentioning

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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“…NS interacts with another nucleolar protein called nucleophosmin (NPM; ref. 17), a well known nucleolar marker and multifunctional phosphoprotein with antiapoptotic properties (18,19) implicated in ribosome biogenesis (20,21) and p53 pathway regulation (22,23). NPM delocalization from nucleoli is widely accepted as a marker of nucleolar stress in noncardiac cells (1,24,25).…”

mentioning

confidence: 99%

Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin

Avitabile

Bailey

Cottage

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Nucleolar stress, characterized by loss of nucleolar integrity, has not been described in the cardiac context. In addition to ribosome biogenesis, nucleoli are critical for control of cell proliferation and stress responses. Our group previously demonstrated induction of the nucleolar protein nucleostemin (NS) in response to cardiac pathological insult. NS interacts with nucleophosmin (NPM), a marker of nucleolar stress with cytoprotective properties. The dynamic behavior of NS and NPM reveal that nucleolar disruption is an early event associated with stress response in cardiac cells. Rapid translocation of NS and NPM to the nucleoplasm and suppression of new preribosomal RNA synthesis occurs in both neonatal rat cardiomyocytes (NRCM) and cardiac progenitor cells (CPC) upon exposure to doxorubicin or actinomycin D. Silencing of NS significantly increases cell death resulting from doxorubicin treatment in CPC, whereas NPM knockdown alone induces cell death. Overexpression of either NS or NPM significantly decreases caspase 8 activity in cultured cardiomyocytes challenged with doxorubicin. The presence of altered nucleolar structures resulting from myocardial infarction in mice supports the model of nucleolar stress as a general response to pathological injury. Collectively, these findings serve as the initial description of myocardial nucleolar stress and establish the postulate that nucleoli acts as sensors of stress, regulating the cellular response to pathological insults.nucleolus | rRNA | hypoxia | hypertrophy

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Nucleophosmin Serves as a Rate-Limiting Nuclear Export Chaperone for the Mammalian Ribosome

Cited by 189 publications

References 57 publications

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

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

Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin

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