New Roles for the Nucleolus in Health and Disease

Villacís, Lorena Núñez; Wong, Mei; Ferguson, Laura L.; Hein, Nadine; George, Amee J.; Hannan, Katherine M.

doi:10.1002/bies.201700233

Cited by 59 publications

(57 citation statements)

References 120 publications

(174 reference statements)

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“…The nucleolus is a highly dynamic, multifunctional, subnuclear organelle [3,4,7]. Its most established role is as the hub of ribosome biogenesis, the process by which rRNA is transcribed, cleaved, and assembled into ribosomes (Figure 1).…”

Section: The Multifunctional Nucleolusmentioning

confidence: 99%

“…This process is broadly termed nucleolar stress and can take many forms, dependent on cell context and the nature of the insult [14,17]. Outcomes associated with nucleolar stress include differentiation, cell cycle arrest, autophagy, DNA repair, senescence, and apoptosis [4,16,18,19].…”

Section: The Multifunctional Nucleolusmentioning

confidence: 99%

“…Aberrant nucleolar activity is causally associated with progression of many common diseases [4,99,100]. For example, hyperactivation induced by oncogenes and tumour suppressors contributes to cancer progression by allowing rapid protein synthesis and through dysregulation of nucleolar stress pathways [16,49].…”

Section: Therapeutic Relevance Of Nucleoli-nf-κb Crosstalk: a Role Inmentioning

confidence: 99%

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Insights into the Relationship between Nucleolar Stress and the NF-κB Pathway

Chen

Stark

2019

Trends in Genetics

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The nuclear organelle the nucleolus and the transcription factor nuclear factor of κ-light-chain-enhancer of activated B cells (NF-κB) are both central to the control of cellular homeostasis, dysregulated in common diseases and implicated in the ageing process. Until recently, it was believed that they acted independently to regulate homeostasis in health and disease. However, there is an emerging body of evidence suggesting that nucleoli and NF-κB signalling converge at multiple levels. Here we will review current understanding of this crosstalk. We will discuss activation of the NF-κB pathway by nucleolar stress and induction of apoptosis by nucleolar sequestration of NF-κB/RelA. We will also discuss the role of TIF-IA, COMMD1, and nucleophosmin, which are key players in this crosstalk, and the therapeutic relevance, particularly with respect to the antitumour effects of aspirin. Nucleoli-NF-κB-Nucleoli: An Emerging Signalling Network There are many parallels between nucleoli and the nuclear factor of κ-light-chain-enhancer of activated B cells (NF-κB) transcription factor. For example, both are stimulated by the same plethora of stresses (Table 1), both regulate the same downstream physiological processes, both are dysregulated in a variety of common diseases which contributes to disease aetiology, and both are implicated in senescence and ageing [1-6]. Until recently, it was believed that these factors act independently to regulate cellular homeostasis in health, ageing, and disease. However, there is a growing body of evidence to suggest that nucleolar stress activates the NF-κB pathway, and that nucleolar sequestration of NF-κB components is a critical apoptotic regulator. Here we will review the various levels of convergence between NF-κB and the nucleolus. We will also discuss the relevance of nucleoli-NF-κB crosstalk to the antitumour mechanisms of aspirin and the potential relevance to senescence and ageing. Highlights Nucleoli play a critical role in maintaining cellular homeostasis in health, ageing, and disease, as does the NF-κB transcription factor pathway. Emerging data suggest that interplay between these two cellular factors regulates cell growth and death. An atypical nucleolar stress response pathway, characterized by degradation of the PolI complex component, TIF-IA, and nucleolar enlargement, lies upstream of NF-κB pathway activation. Components of the NF-κB complex accumulate in nucleoli in response to stress. The presence of RelA in nucleoli triggers cytoplasmic relocation of nucleophosmin which mediates apoptosis by transporting BAX to mitochondria.

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Section: The Multifunctional Nucleolusmentioning

confidence: 99%

Section: The Multifunctional Nucleolusmentioning

confidence: 99%

Section: Therapeutic Relevance Of Nucleoli-nf-κb Crosstalk: a Role Inmentioning

confidence: 99%

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Insights into the Relationship between Nucleolar Stress and the NF-κB Pathway

Chen

Stark

2019

Trends in Genetics

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“…In addition, decreased levels of some Drosophila RPs result in overgrowth of specific tissues and melanotic tumors (Goudarzi, Lind ström, 2016). Mutations in genes encoding RPs and ribosome biogenesis factors lead to a series of congenital human disorders collectively called ribosomopathies, and predispose to cancer (Narla, Ebert, 2010;Henras et al, 2015;Mills, Green, 2017;Núñez Villacís et al, 2018). In some cases, these diseases are also caused by haploinsufficiency for these genes caused by somatic mutations (Narla, Ebert, 2010;Núñez Villacís et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Non3 is an essential Drosophila gene required for proper nucleolus assembly

et al. 2019

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The nucleolus is a dynamic non-membrane-bound nuclear organelle, which plays key roles not only in ribosome biogenesis but also in many other cellular processes. Consistent with its multiple functions, the nucleolus has been implicated in many human diseases, including cancer and degenerative pathologies of the nervous system and heart. Here, we report the characterization of the Drosophila Non3 (Novel nucleolar protein 3) gene, which encodes a protein homologous to the human Brix domain-containing Rpf2 that has been shown to control ribosomal RNA (rRNA) processing. We used imprecise P-element excision to generate four new mutant alleles in the Non3 gene. Complementation and phenotypic analyses showed that these Non3 mutations can be arranged in an allelic series that includes both viable and lethal alleles. The strongest lethal allele (Non3∆600) is a genetically null allele that carries a large deletion of the gene and exhibits early lethality when homozygous. Flies heterozygous for Non3∆600 occasionally exhibit a mild reduction in the bristle size, but develop normally and are fertile. However, heteroallelic combinations of viable Non3 mutations (Non3197, Non3310 and Non3259) display a Minute-like phenotype, consisting in delayed development and short and thin bristles, suggesting that they are defective in ribosome biogenesis. We also demonstrate that the Non3 protein localizes to the nucleolus of larval brain cells and it is required for proper nucleolar localization of Fibrillarin, a protein important for post-translational modification and processing of rRNAs. In summary, we generated a number of genetic and biochemical tools that were exploited for an initial characterization of Non3, and will be instrumental for future functional studies on this gene and its protein product.

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“…This process includes transcription of ribosomal DNA (rDNA), maturation of ribosomal RNA primary transcript (pre-rRNA), as well as assembly of ribosomal subunits and their transport to the cytoplasm (Olson and Dundr 2015; Raška et al 2004; Stępiński 2014). In addition, they participate in many important cellular functions, including those responsible for health and disease (Núñez Villacís et al 2018), and stress response and development. This concerns both animals (Lindström et al 2018; Tsai and Pederson 2014; Tsekrekou et al 2017) and plants (Kalinina et al 2018; Ohbayashi and Sugiyama 2018).…”

Section: Introductionmentioning

confidence: 99%

The nucleolus, an ally, and an enemy of cancer cells

Stępiński

2018

Histochem Cell Biol

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The rates of ribosome production by a nucleolus and of protein biosynthesis by ribosomes are tightly correlated with the rate of cell growth and proliferation. All these processes must be matched and appropriately regulated to provide optimal cell functioning. Deregulation of certain factors, including oncogenes, controlling these processes, especially ribosome biosynthesis, can lead to cell transformation. Cancer cells are characterized by intense ribosome biosynthesis which is advantageous for their growth and proliferation. On the other hand, this feature can be engaged as an anticancer strategy. Numerous nucleolar factors such as nucleolar and ribosomal proteins as well as different RNAs, in addition to their role in ribosome biosynthesis, have other functions, including those associated with cancer biology. Some of them can contribute to cell transformation and cancer development. Others, under stress evoked by different factors which often hamper function of nucleoli and thus induce nucleolar/ribosomal stress, can participate in combating cancer cells. In this sense, intentional application of therapeutic agents affecting ribosome biosynthesis can cause either release of these molecules from nucleoli or their de novo biosynthesis to mediate the activation of pathways leading to elimination of harmful cells. This review underlines the role of a nucleolus not only as a ribosome constituting apparatus but also as a hub of both positive and negative control of cancer development. The article is mainly based on original papers concerning mechanisms in which the nucleolus is implicated directly or indirectly in processes associated with neoplasia.

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New Roles for the Nucleolus in Health and Disease

Cited by 59 publications

References 120 publications

Insights into the Relationship between Nucleolar Stress and the NF-κB Pathway

Insights into the Relationship between Nucleolar Stress and the NF-κB Pathway

Non3 is an essential Drosophila gene required for proper nucleolus assembly

The nucleolus, an ally, and an enemy of cancer cells

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