Nucleolus: the fascinating nuclear body

Sirri, Valentina; Urcuqui-Inchima, Silvio; Roussel, Pascal; Hernandez‐Verdun, Danièle

doi:10.1007/s00418-007-0359-6

Cited by 342 publications

(340 citation statements)

References 200 publications

(235 reference statements)

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“…The expression levels of these proteins correlate with the tumorigenicity of MCF-7 cells that express mutant p14. In recent years, it has been established that in addition to its role in rRNA synthesis and ribosome biogenesis, the nucleolus is involved in a variety of cellular functions, including regulation of the cell cycle, senescence, gene silencing, and sensing of cellular stress (26)(27)(28)(29)(30)(31), as well as in viral replication (32,33). The relationship between the nucleolus, ribosome biogenesis, and cancer has been the topic of a recent review (34), in which some evidence to that effect has been documented.…”

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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“…This membraneless organelle is considered a dynamic structure (4,84), where protein complexes are continuously exchanged with the nucleoplasm. Its classical tripartite organization has been dissected using electron microscopy and reflects the different steps of ribosomal biogenesis (130): (i) the fibrillar center, where the RNA polymerase I (Pol I) transcription starts; (ii) the dense fibrillar component, where the initial stages of pre-rRNA processing occur and (iii) the granular component involved in the late processing steps (62). Transcription of the ribosomal DNA (rDNA) repeats generates a 47S pre-rRNA precursor that is further cleaved and processed into 28S, 18S, and 5.8S rRNAs and concomitantly assembled into large and small ribosomal subunits together with the 5S rRNA molecules (18, 32a).…”

Section: Structure Composition and Classical Functions Of The Nuclementioning

confidence: 99%

“…Transcription of the ribosomal DNA (rDNA) repeats generates a 47S pre-rRNA precursor that is further cleaved and processed into 28S, 18S, and 5.8S rRNAs and concomitantly assembled into large and small ribosomal subunits together with the 5S rRNA molecules (18, 32a). These complex series of events is controlled, in yeast, by roughly 150 small nucleolar RNAs (snoRNAs) and two large ribonucleoprotein complexes, named small subunit processosome (for the 40S ribosomal subunit) and large subunit processosome (for the 60S ribosomal subunit) (130). Two types of nucleotide modifications (2¢-O-methylation and pseudouridylation) are introduced during the maturation process by snoRNAs belonging to the box C/D or box H/ACA families and mediate endonucleolytic cleavages of pre-RNAs (130, 32a).…”

Section: Structure Composition and Classical Functions Of The Nuclementioning

confidence: 99%

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Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

Antoniali

Lirussi

Poletto

et al. 2014

Antioxidants & Redox Signaling

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Significance: An emerging concept in DNA repair mechanisms is the evidence that some key enzymes, besides their role in the maintenance of genome stability, display also unexpected noncanonical functions associated with RNA metabolism in specific subcellular districts (e.g., nucleoli). During the evolution of these key enzymes, the acquisition of unfolded domains significantly amplified the possibility to interact with different partners and substrates, possibly explaining their phylogenetic gain of functions. Recent Advances: After nucleolar stress or DNA damage, many DNA repair proteins can freely relocalize from nucleoli to the nucleoplasm. This process may represent a surveillance mechanism to monitor the synthesis and correct assembly of ribosomal units affecting cell cycle progression or inducing p53-mediated apoptosis or senescence. Critical Issues: A paradigm for this kind of regulation is represented by some enzymes of the DNA base excision repair (BER) pathway, such as apurinic/apyrimidinic endonuclease 1 (APE1). In this review, the role of the nucleolus and the noncanonical functions of the APE1 protein are discussed in light of their possible implications in human pathologies. Future Directions: A productive cross-talk between DNA repair enzymes and proteins involved in RNA metabolism seems reasonable as the nucleolus is emerging as a dynamic functional hub that coordinates cell growth arrest and DNA repair mechanisms. These findings will drive further analyses on other BER proteins and might imply that nucleic acid processing enzymes are more versatile than originally thought having evolved DNA-targeted functions after a previous life in the early RNA world. Antioxid. Redox Signal. 20, 621-639.

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“…20 When observed at electron microscopy, the nucleolus is morphologically divided into three main components that reflect the multi-step ribosome biogenesis process: the fibrillar centres (containing DNA sequences encoding ribosomal RNA); 38 the dense fibrillar component (in which nascent pre-rRNA transcripts enter to undergo a series of early processing steps); and the granular component, radiating out from the dense fibrillar component, in which intermediate or late stages of RNA maturation occur. 39 Notably, nucleophosmin expression is restricted to the granular component, 20 reflecting its involvement in later processing and assembly steps and in ribosomal subunit export. 40 At first glance, the restricted NPM1wt nucleolar localization appears surprising in the light of its continual shuttling between nucleus and cytoplasm.…”

Section: Native Npm1 Is a Nucleolar Protein With Ubiquitous Tissue Exmentioning

confidence: 99%

Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications

et al. 2009

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Nucleophosmin (NPM1) is a highly conserved nucleo-cytoplasmic shuttling protein that shows a restricted nucleolar localization. Mutations of NPM1 gene leading to aberrant cytoplasmic dislocation of nucleophosmin (NPMc þ ) occurs in about one third of acute myeloid leukaemia (AML) patients that exhibit distinctive biological and clinical features. We discuss the latest advances in the molecular basis of nucleophosmin traffic under physiological conditions, describe the molecular abnormalities underlying altered transport of nucleophosmin in NPM1-mutated AML and present evidences supporting the view that cytoplasmic nucleophosmin is a critical event for leukaemogenesis. We then outline how a highly specific immunohistochemical assay can be exploited to diagnose NPM1-mutated AML and myeloid sarcoma in paraffin-embedded samples by looking at aberrant nucleophosmin accumulation in cytoplasm of leukaemic cells. This procedure is also suitable for detection of haemopoietic multilineage involvement in bone marrow trephines. Moreover, use of immunohistochemistry as surrogate for molecular analysis can serve as first-line screening in AML and should facilitate implementation of the 2008 World Health Organization classification of myeloid neoplasms that now incorporates AML with mutated NPM1 (synonym: NPMc þ AML) as a new provisional entity. Finally, we discuss the future therapeutic perspectives aimed at reversing the altered nucleophosmin transport in AML with mutated NPM1.

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Nucleolus: the fascinating nuclear body

Cited by 342 publications

References 200 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

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications

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