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It can also induce other factors involved in autophagy, DNA repair and metabolism [94]. Ribosomal proteins RPs regulating transcription factors TFs. Their downregulation or decreased transcriptional activities by RPs mediate cellular stress responses via altered transcription of target genes. The oncoprotein c-Myc positively controls cell growth and proliferation [] and serves as a direct regulator of ribosome biogenesis; many products of its transcriptional target genes are involved in ribosome biogenesis [].

RPS14 may also function as a negative regulator of c-Myc []. Consistently, upon nucleolar stress, as ribosome-free RPs, these proteins can lead to inhibition of cell proliferation through suppression of c-Myc and its target gene expression []. E2F-1 is a member of the E2Fs family of transcription factors; the expression of their target genes are important both for cell proliferation and apoptosis []. Recently, RPL3 has been found as a pro-apoptotic factor under nucleolar stress induced by 5-fluorouracil in colon cancer cells devoid of p Consequently, apoptosis is induced through the mitochondrial apoptotic cell death pathway [98].

There are several nucleolar proteins that bypass p53 and directly promote cell cycle arrest or apoptosis. Both NPM1 and ARF are well-known for their roles in p53 signaling, however, several reports have demonstrated their involvement in pindependent signaling []. In these cases, translocation of the nucleolar proteins and their interactions with the corresponding proteins may be analyzed.

Interestingly, many RP or other nucleolar protein-mediated pindependent stress responses require NPM1. In fact, NPM1 alone also interacts with apoptotic proteins. In conditions of nucleolar stress, NPM1 is transcriptionally induced and relocalizes from the nucleolus to the cytoplasm where it complexes with BAX, a crucial effector of the mitochondrial apoptosis pathway.

Of note, cytosolic NPM1-BAX interaction has also been associated with cell resistance to death stimuli [] , therefore, the cellular response this direct interaction of NPM1 with apoptosis regulators does not necessarily result in cell death. The Wnt target Peter Pan PPAN localizes to mitochondria in addition to its nucleolar localization and inhibits the mitochondrial apoptosis pathway in a pindependent manner.

Its role as an anti-apoptotic factor is indicated by the fact that knockdown of PPAN induces BAX stabilization, mitochondrial membrane depolarization and cytochrome c release. Staurosporine or Act. D-induced nucleolar stress and apoptosis disrupt nucleolar PPAN localization and induce its accumulation in the cytoplasm, which might be associated with impairment in its anti-apoptotic function [].

Recently, the nuclear mitotic apparatus protein NuMA that locates in nucleoli in the interphase, has been demonstrated to be redistributed upon Act. D or doxorubicin- induced nucleolar stress. Downregulation of NuMA expression triggers nucleolar stress, as shown by decreased nascent pre-rRNA synthesis, fibrillarin perinucleolar cap formation and upregulation of p27kip1, but not p53 []. Several studies reported that ARF binds and antagonizes the transcriptional activities of c-Myc and E2F-1, halting cell cycle progression in absence of p53 [].

Cumulative findings that any impairment in ribosome biogenesis by various insults can lead to p53 stabilization and activation, has led to the hypothesis that a low p53 level under non-stress condition relies on normal homeostasis of ribosome biogenesis in the nucleolus.

This default state is ensured by the intactness of the ribosome biogenesis procedures and nucleolar structure. The evidence supporting this default model is robust, as p53 activation in nucleolar stress can be induced by the aberrant expression of those nucleolar proteins that are indispensable for ribosome biogenesis, or by various stimuli.

This notion then brought up an outstanding question how the errors or hurdles within the nucleolus signal to p We here summarize several aspects of studies addressing this question [30] [48] [97] [] , including some frequent confusions or ambiguities. In response to nucleolar stress, several RPs bind to MDM2 and block MDM2-mediated p53 ubiquitination and degradation, resulting in p53 stabilization and activation. After cells are exposed to low doses of Act. Therefore, the RP-MDM2-p53 signaling pathway has been proposed and believed to constitute a surveillance network monitoring the integrity of ribosomal biogenesis [].

If an increased binding of free RPs with MDM2 is a prerequisite for this monitoring or sensing, the questions arises where these increased free RPs come from under nucleolar stress conditions, and in which subnuclear compartment they interact with MDM2, given that RPs mostly reside in the nucleolus and the cytoplasm, whereas MDM2 often stays in the nucleoplasm. However, these critical points have not been paid adequate attention to, and thus remain unclear. And secondly, the reported findings were controversial and highly context-dependent:.

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The early work by Lohrum et al. When expressed alone, L11 was predominantly nucleolar and HDM2 confined to the nucleoplasm, but 24 hours after co-transfection, L11 and HDM2 were both localized to the nucleoplasm when the LHDM2 ratio was low ; or both localized to the nucleolus when L11 levels were higher However, again under ectopic expression, in response to nucleolar stress induced by low levels of Act. Apparently, one is hardly able to draw conclusions from these observations that L11 is released from the nucleolus to the nucleoplasm upon stress.

Bursac et al. Using cell fractionation to purify the nucleolus extract, they found that endogenous nucleolar L5 and L11 were not reduced upon Act. D treatment, and using YFP-L11 transfection and fibrillarin immunostaining, they found that L11 was not translocated to the nucleoplasm upon Act. D treatment.

The authors claimed that whereas several other newly synthesized ribosomal proteins are degraded by the proteasome upon Act. Furthermore, the endogenous, newly synthesized L5 and L11 continued to be imported into nucleoli even after nucleolar disruption and co-localized with MDM2, p53, and PML. Therefore, in contrast to findings by others, their results suggest that the disrupted nucleoli may provide a platform for L5- and Ldependent p53 activation. Recently, using immunostaining, Kayama et al.

D treatment []. In our experiments, immunostaining of RPL11 in U2OS cells showed a predominant location in the cytoplasm and no redistribution to the nucleoli or nucleoplasm was detectable upon Act. D-induced nucleolar stress unpublished data. A number of review articles stated or implied that the increased levels of ribosome-free RPs may originate from disrupted nucleoli [97] [].

To our knowledge, this notion lacks direct evidence, and thus remains speculative, unless free endogenous RP translocation from the nucleolus is detected under specific or general stress conditions. An increased RPs-MDM2 interaction could follow diverse cellular disturbances, such as global translation inhibition [] , or the breakdown of ribosomal polysomes in the cytoplasm [33] [43] []. One can predict that there would be an accumulation of free RPs in the cells under these circumstances.

Taken together, it is worth further investigating how free RPs sense the nucleolar stress and then transmit signals to p ARF alternative reading frame protein, p19 in mouse, p14 in humans induces p53 activation in response to certain types of DNA damage [] or several ontogenetic stresses [] [] [] , and is therefore categorized as a tumor suppressor.

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ARF is considered to localize to nucleoli of non-stressed cells []. As a basic nucleolar protein rich in arginine residues, it binds to multiple ribosomal proteins, and participates in 47S rRNA transcription and 32S processing events []. Although several studies revealed that ARF was released to nucleoplasm under nucleolar stress and targeted the central acidic domain of MDM2 to inhibit p53 degradation [] [] , some other reports implied that a resident nucleoplasmic fraction of total ARF is involved in the interaction with MDM2 under stress conditions [] [].

Moreover, some studies indicated that ARF is dispensable for nucleolar stress-induced p53 accumulation [] []. In our study [31] , we found that endogenous or exogenous ARF was similarly distributed both in the nucleolus and nucleoplasm of U2OS cells; the nucleolar ARF did not move out following Act.

The wide range of stress conditions which provoke NPM1 translocation [16] [31] [] [] might explain how p53 can integrate various stimuli. In our own work, we aimed at answering the question, if the translocated, nucleoplasmic fraction of NPM1 was the sole trigger for p53 activation. Therefore, we constructed an NPM1 mutant, unable to move upon Act. In contrast to wild-type NPM1, this mutant was unable to disrupt the pHDM2 interaction, and thus greatly compromised the activation of p53 [31].

However, after cells were exposed to Act. An enhanced p53 accumulation was observed when wild-type NPM1 was restored, but reintroducing the unmovable mutant NPM1 could not cause an increase of p A co-immunoprecipitation assay showed that the disruption of the HDM2-p53 interaction occurred in the cells bearing the wild-type but not mutant NPM1, whereas amounts of ARF bond to HDM2 appeared similar in both cell groups. These data suggest that the nucleoplasmic fraction of ARF alone is able to induce p53 accumulation under basal conditions.

However, further p53 accumulation under stress conditions is determined by the presence of the nucleoplasmic NPM1, independent of ARF. Collectively, the binding of ribosomal proteins or ARF with HDM2, which had been thought to be sufficient for p53 stabilization [33] [] [] [] , is actually insufficient when NPM1 stays within the nucleoli. These results highlight that nucleoplasmic translocation of NPM1 is a prerequisite for stress-induced activation of p As discussed above, nucleoplasmic translocation of NPM1 is the most prominent hallmark of nucleolar stress.

However, the upstream causes of this translocation remained unclear. In other words, how various cellular insults trigger NPM1 translocation had not been ever asked. Using single live-cell imaging and the redox biosensors, we demonstrated that nucleolar oxidation is a general response to various cellular stresses and a trigger for NPM1 translocation. This conclusion was supported by that antioxidant N-acetyl-cystein pretreatment was able to prevent the NPM1 translocation to a great extent, while treatment with a protein reducing agent completely inhibited NPM1 translocation.

We showed that during nucleolar oxidation, NPM1 undergoes S-glutathionylation on cysteine , which triggers the dissociation of NPM1 from nucleolar nucleic acids. Accordingly, the NPM1 CS mutant, unable to be glutathionylated, remained in the nucleolus under nucleolar stress, and greatly compromised the activation of p In sum, our findings provide a redox mechanism underlying the nucleolar stress sensing by NPM1 [31] Figure 4. Nucleolar oxidation is a general response to nucleolar stress.

S-glutathionylation and nucleoplasmic translocation of NPM1 are indispensable for p53 activation in nucleolar stress [31]. These diseases usually have dramatic systemic phenotypes and severe outcomes [] [] [] [] [] [] [] []. Of note, although ribosomopathies display nucleolar stress, there are no therapeutic options directly targeting nucleolar stress to delay disease progression. Despite the fact that these disorders are polycausal, nucleolar stress may be one of the significant mediators in the degeneration or loss of neurons [].

Besides morphological and functional manifestations in tissues and cell culture, the direct causal relation between these diseases and nucleolar stress has been established using the TIF-IA mouse model see below [79] []. A related application, aiming to alleviate nucleolar stress for the prevention and treatment of these disorders will likely ensue. Large and abnormal nucleoli are commonly observed in cancer cells [].

The hyperactivation of ribosome biogenesis likely contributes to increased cancer cell survival and proliferation. In addition, cancer treatment faces challenges in chemo-radio-resistance cancers and those insensitive to other killing approaches. Potentiating nucleolar stress in these cancer cells may be a novel therapeutic strategy.

Indeed, some typical nucleolar stress-inducing agents are under clinical investigation for remedy of leukemia, which has shown promising outcomes [] []. Hereafter, we present a brief overview on these two types of nucleolar stress-related diseases. We recommend several comprehensive and in-depth reviews [] [] [] [] , and try to provide some updated information. Neurodegenerative disorders are chronic diseases, characterized by the progressive loss of specific neurons in the central or peripheral nervous system.

These diseases are characterized by degeneration or loss of a specific subpopulation of neurons. Nucleolar stress is an emerging element of the degenerative process, caused by impaired rRNA transcription and altered nucleolar integrity []. PD is associated with the loss of dopaminergic DA neurons. Reduced nucleolar volume usually reflects reduced rRNA synthesis, while reduced rRNA synthesis has been reported in neurodegenerative disorders [].

Early data show that nucleolar volume in DA neurons is decreased in PD patients and this is inversely correlated with disease duration [] []. Decreased nucleolar volume has been reported in the partial unilateral intrastriatal 6-hydroxydopamine oxidative stress rat model of PD [81]. Along these lines, a pharmacological mouse model of PD displays disruption of nucleolar integrity [79] , while there is also a significant atrophy of the nucleoli in AD [80].

Interestingly, DNA damage in neurons can cause NPM1 translocation to the nucleoplasm [] , thus eliciting another hallmark of nucleolar stress. Mouse models for conditional knockout KO of the transcription factor TIF-IA have been generated, in which nucleolar stress is induced in specific neuronal populations at a defined time-point [44]. Therefore, mice with conditional KO of TIF-IA not only confirmed a causal correlation of nucleolar stress with neuronal degeneration, but also served as an efficient model to study nucleolar stress itself.

Cell-specific TIF-IA KO in distinct postmitotic neurons resulted in their slow, progressive degeneration, showing that neurons can survive for several months under nucleolar stress [79] [] [] []. This slow progression allows the analysis of the sequence of events triggered by nucleolar stress in distinct neuronal populations.

Notably, nucleolar impairment at the age of two months in DA neurons leads to mitochondrial dysfunction and increased oxidative damage, characteristics shared by various neurodegenerative diseases, such as PD, AD and HD. It could trigger a neuroprotective defense response at early stages, probably through inducing autophagy [] and pdependent antioxidant response [] , but, on the long run, lead to impaired mitochondrial function and increased oxidative stress, and ultimately neuronal death [79] [].

Further dissection of the regulatory factors in nucleolar stress at a temporal resolution may help to better understand the pathophysiology of neurodegenerative disorders and create novel interfering strategies for prevention and treatment. Given the pivotal role of NPM1 in nucleolar stress transmission to p53, one of the main tumorsuppressors, there are multiple NPM1-based therapeutic strategies for cancer treatment. Indeed, a vast part of anticancer drugs triggers apoptotic cell death through pactivation pathway.

Because of a causal relationship between anticancer chemical drug induced cell apoptosis and NPM1 translocation [63] [] [] , NPM1 translocation could be regarded as a effective drug screening marker for novel antitumor agents selection [8]. As a safe and tolerable drug in clinical phase II trial, CIGB exerts a broad original and synergistic antiproliferative effect on different cell lines [] [] [] []. Perera et al. Additionally, there are also some selective Pol I inhibitors that reveal promising clinical effects [] [].

For example, CX exhibits broad anti-proliferative and apoptotic effects on cancer cells and demonstrated impressive anti-tumor growth properties in xenograft models of breast and pancreatic cancer []. Intriguingly, the next generation of CX, CX showed effectiveness in human cancer cells that experience overloaded ribosomal biogenesis compared to normal cells [] [].

The cytotoxic marine natural product Avrainvillamide specifically binds the C-terminus of NPM1 and leads to its disassociation from nucleolar nucleic acid [] []. Both of them caused NPM1 nucleoplasmic translocation. Because the NPM1 C-terminal domain surface is responsible for NPM1 nucleolar localization [] , it is likely that these two C-terminus targeting compounds are also related with nucleolar stress. Additionally, there are some compounds targeting other NPM1 functional domains. These NPM1-targeting compounds both showed excellent anticancer effects.

Importantly, both of them induced increased p53 levels and trancriptional activity, although their effects on NPM1 localization has not been investigated so far. Immunohistochemical staining in bone marrow specimens reveals a constant cytoplasmic localization for NPM1 [].


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In addition, this mutant also causes a cytoplasmic retention effect of wild-type NPM1, leaving only trace amounts of wild-type NPM1 in the nucleoli []. Thus, Falini et al. D induced nucleolar stress and utilized the clinical recommended dose of Act. Three of them showed hematologic complete remission within six weeks of therapy, and one of them even manifested molecular complete remission lasting for 14 months [].

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    Gilkes, L. Chen, and J. Yuan, Y. Zhou, E. Casanova, M. Chai, E. Kiss, H. Golomb, D. Bublik, S. Wilder, R. Nevo, V. Kiss, K. Grabusic, S. Volarevic, and M. Nicolas, P. Parisot, C. Pinto-Monteiro, R. De Vleeschouwer, and D. Lafontaine, "Involvement of human ribosomal proteins in nucleolar structure and pdependent nucleolar stress", Nature Communications , vol. Perry, and D. Suzuki, R. Kogo, K. Kawahara, M. Sasaki, M. Nishio, T. Maehama, T. Sasaki, K. Mimori, and M. Boulon, B. Westman, S. Hutten, F. Boisvert, and A. Yung, E. Hui, and P.

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