Ribosomal Proteins Control or Bypass p53 during Nucleolar Stress

Russo, Annapina; Russo, Giulia

doi:10.3390/ijms18010140

Cited by 126 publications

(153 citation statements)

References 96 publications

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“…For example, NPM1 is able to interact directly with MDM2, independently of ARF, to inhibit p53/MDM2 and protect p53 from degradation (Kurki et al, 2004). Moreover, NPM1 has also been reported to directly associate with p53 for p53 stabilization and activation (Lambert and Buckle, 2006;Russo and Russo, 2017). We observed that NPM1 and p53 levels increased following the ribosomal stress caused by RGNNV infection.…”

Section: Discussionmentioning

confidence: 66%

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RGNNV-induced cell cycle arrest at G1/S phase enhanced viral replication via p53-dependent pathway in GS cells

et al. 2018

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Nervous necrosis virus (NNV) is a ubiquitous pathogen in the aquaculture worldwide. Little is known about the relationship between NNV virus and host cells. Our studies showed that RGNNV infection could induce cell cycle arrest via activation of p53 signaling in cultured host cells. Infection of RGNNV redistributed NPM1, stabilized p53 and inhibited cell proliferation by inducing G1 arrest. RGNNV infection also led to phosphorylation and accumulation of p53 in a time-dependent manner. Furthermore, RGNNV infection upregulated cyclin-dependent kinase inhibitor 1 A (p21) and downregulated cyclin E and cyclin-dependent kinase 2 (CDK2). The expression of genes in the p53 pathway did not change significantly after p53 knockdown by pifithrin-α during RGNNV infection. However, NPM1 knockdown could abrogate RGNNV-induced cell proliferation inhibition, activation of p53 signaling and cell cycle arrest. In addition, RGNNV infection of the cells synchronized in various stages of cell cycle showed that viral genomic RNA and virus titer were higher in the cells released from G1 phase- or S phase-synchronized cells than that in the cells released from the G2 phase-synchronized or asynchronous cells after 18 h p.i. Therefore, our study reveals that RGNNV infection induces the p53-dependent pathway, resulting in a cell cycle arrest at G1 phase in host cells, which might provide a favorable condition for viral replication.

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Section: Discussionmentioning

confidence: 66%

“…The redistribution of nucleolar proteins plays an important role in nucleolar/ribosomal stress response (Russo and Russo, 2017). GS cells infected RGNNV were fixed at 24 h and the intracellular localization of RGNNV capsid protein and NPM1 were examined by indirect immunofluorescence (Fig.…”

Section: Rgnnv Induces Nucleolar/ribosomal Stress In Gs Cellsmentioning

confidence: 99%

RGNNV-induced cell cycle arrest at G1/S phase enhanced viral replication via p53-dependent pathway in GS cells

et al. 2018

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“…Thus, only other nucleolar factors involved in the activation of appropriate pathways are taken into consideration. There is a growing body of evidence that RPs help to cope with unwelcome cells through their participation in pathways with or without p53 in response to the disruption of nucleolar function and integrity (Liu et al 2017b; Russo and Russo 2017). Recent studies point to the fact that RPs exhibit certain regularity of action during either fight with or generation of cancers.…”

Section: A Nucleolus As An Opponent Of Cancer Cells Via P53-dependentmentioning

confidence: 99%

“…Different proteins whose expression changes during stress as well as those nucleolar or ribosomal proteins which are released from nucleoli as a result of stress-induced nucleolar disintegration may contribute to the activation of pathways eliminating undesired cells. The mechanisms associated with activation of both pathways dependent on (Vlatkovic et al 2014) and independent of p53 (Chen et al 2016a; Russo and Russo 2017) participate in the nucleolar surveillance response. Since more than half of human cancers are devoid of functional p53 (Soussi 2000), it is especially important to find the p53-independent anticancer pathways.…”

Section: Nucleolus-mediated Anticancer Strategiesmentioning

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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“…Specifically, upon 5-FU induced nucleolar stress, a subset of rp including uL18 (rpL5), uL5 (rpL11), and uL14 (rpL23) are released from the ribosome to activate p53 through MDM2 inhibition [10]. Recently, our studies focused on post-transcriptional regulation [11,12,13,14] and extra-ribosomal functions of ribosomal proteins [11,15]. In particular, we demonstrated that uL3 (formerly rpL3) [16] is involved in the regulation of its own expression by regulating the splicing of its own transcript [17,18].…”

Section: Introductionmentioning

confidence: 99%

Role of uL3 in Multidrug Resistance in p53-Mutated Lung Cancer Cells

Russo

Saide

Smaldone

et al. 2017

IJMS

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Cancer is one of the most common causes of death among adults. Chemotherapy is crucial in determining patient survival and quality of life. However, the development of multidrug resistance (MDR) continues to pose a significant challenge in the management of cancer. In this study, we analyzed the role of human ribosomal protein uL3 (formerly rpL3) in multidrug resistance. Our studies revealed that uL3 is a key determinant of multidrug resistance in p53-mutated lung cancer cells by controlling the cell redox status. We established and characterized a multidrug resistant Calu-6 cell line. We found that uL3 down-regulation correlates positively with multidrug resistance. Restoration of the uL3 protein level re-sensitized the resistant cells to the drug by regulating the reactive oxygen species (ROS) levels, glutathione content, glutamate release, and cystine uptake. Chromatin immunoprecipitation experiments and luciferase assays demonstrated that uL3 coordinated the expression of stress-response genes acting as transcriptional repressors of solute carrier family 7 member 11 (xCT) and glutathione S-transferase α1 (GST-α1), independently of Nuclear factor erythroid 2-related factor 2 (Nrf2). Altogether our results describe a new function of uL3 as a regulator of oxidative stress response genes and advance our understanding of the molecular mechanisms underlying multidrug resistance in cancers.

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Ribosomal Proteins Control or Bypass p53 during Nucleolar Stress

Cited by 126 publications

References 96 publications

RGNNV-induced cell cycle arrest at G1/S phase enhanced viral replication via p53-dependent pathway in GS cells

RGNNV-induced cell cycle arrest at G1/S phase enhanced viral replication via p53-dependent pathway in GS cells

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

Role of uL3 in Multidrug Resistance in p53-Mutated Lung Cancer Cells

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