The nucleolus fine-tunes the orchestration of an early neuroprotection response in neurodegeneration

Erickson, Jeffrey D.; Bazán, Nicolás G.

doi:10.1038/cdd.2013.107

Cited by 9 publications

(4 citation statements)

References 21 publications

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“…Upon cell stress, P53 is stabilised via several mechanisms (Fig. 6); it is deubiquitinated by ubiquitin carboxyl-terminal hydrolase 1 (USP1), thus rescuing it from degradation and increasing its activity [236], its activator peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) can be phosphorylated by other DNA damage-activated kinases, such as ataxia telangiectasia mutated (ATM) and homeodomain-interacting protein kinase 2 (HIPK2), which then leads to a conformational change in P53 that promotes its accumulation [237][238][239][240] and its inhibitor, MDM2, is impaired, therefore preventing the promotion of P53 proteasomal degradation [36,241]. In addition, active P53 translocates to cell nuclei where it can then enhance its own expression [36].…”

Section: P53mentioning

confidence: 99%

Kinase Signalling in Huntington's Disease

Bowles

Jones

2014

Journal of Huntington's Disease

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Alterations in numerous signal transduction pathways and aberrant activity of specific kinases have been identified in multiple cell and mouse models of Huntington's disease (HD), as well as in human HD brain. The balance and integration of a network of kinase signalling pathways is paramount for the regulation of a wide range of cellular and physiological processes, such as proliferation, differentiation, inflammation, neuronal plasticity and apoptosis. Unbalanced activity within these pathways provides a potential mechanism for many of the pathological phenotypes associated with HD, such as transcriptional dysregulation, inflammation and ultimately neurodegeneration. The characterisation of aberrant kinase signalling regulation in HD has been inconsistent and may be a result of failure to consider integration between multiple signalling pathways, as well as alterations that may occur over time with both age and disease progression. Collating the information about the effect of mHTT on signalling pathways demonstrates that it has wide ranging effects on multiple pro-and anti-apoptotic kinases, resulting in the dysregulation of numerous complex interactions within a dynamic network.

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Section: P53mentioning

confidence: 99%

Kinase Signalling in Huntington's Disease

Bowles

Jones

2014

Journal of Huntington's Disease

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“…However, it is not clear whether the nuclear phosphorylated tau accumulates in the nucleolus and whether the species of tau localised to the nucleolus behaves like nucleolar proteins, such as nucleophosmin (B3) and fibrillarin (FBL) which become redistributed during nucleolar stress [ 19 ]. Nucleolar stress is thought to be an early event in cellular dyshomeostasis, preceding apoptosis and occurs in neurodegeneration [ 2 , 8 , 40 , 44 ].…”

Section: Introductionmentioning

confidence: 99%

The involvement of tau in nucleolar transcription and the stress response

Maina

Bailey

Wagih

et al. 2018

acta neuropathol commun

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Tau is known for its pathological role in neurodegenerative diseases, including Alzheimer’s disease (AD) and other tauopathies. Tau is found in many subcellular compartments such as the cytosol and the nucleus. Although its normal role in microtubule binding is well established, its nuclear role is still unclear. Here, we reveal that tau localises to the nucleolus in undifferentiated and differentiated neuroblastoma cells (SHSY5Y), where it associates with TIP5, a key player in heterochromatin stability and ribosomal DNA (rDNA) transcriptional repression. Immunogold labelling on human brain sample confirms the physiological relevance of this finding by showing tau within the nucleolus colocalises with TIP5. Depletion of tau results in an increase in rDNA transcription with an associated decrease in heterochromatin and DNA methylation, suggesting that under normal conditions tau is involved in silencing of the rDNA. Cellular stress induced by glutamate causes nucleolar stress associated with the redistribution of nucleolar non-phosphorylated tau, in a similar manner to fibrillarin, and nuclear upsurge of phosphorylated tau (Thr231) which doesn’t colocalise with fibrillarin or nucleolar tau. This suggests that stress may impact on different nuclear tau species. In addition to involvement in rDNA transcription, nucleolar non-phosphorylated tau also undergoes stress-induced redistribution similar to many nucleolar proteins.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0565-6) contains supplementary material, which is available to authorized users.

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“…Nucleoplasmic translocation of NPM1 is necessary for p53 activation during nucleolar stress. Emerging evidences show that the nucleolus plays a critical role in neuronal development and maintenance, and nucleolar dysfunction has been involved in neurodegenerative diseases 73 – 75 . Nuclear export of NPM1 to cytoplasm is required for cellular proliferation, while its translocation to the nucleoplasm leads to death through abortive cell cycle induction 76 .…”

Section: Discussionmentioning

confidence: 99%

Roniciclib down-regulates stemness and inhibits cell growth by inducing nucleolar stress in neuroblastoma

Ognibene

Pezzolo

2020

Sci Rep

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Neuroblastoma, an embryonic tumor arising from neuronal crest progenitor cells, has been shown to contain a population of undifferentiated stem cells responsible for the malignant state and the unfavorable prognosis. Although many previous studies have analyzed neuroblastoma stem cells and their therapeutic targeting, this topic appears still open to novel investigations. Here we found that neurospheres derived from neuroblastoma stem-like cells showed a homogeneous staining for several key nucleolar proteins, such as Nucleolin, Nucleophosmin-1, Glypican-2 and PES-1. We investigated the effects of Roniciclib (BAY 1000394), an anticancer stem cells agent, on neurospheres and on an orthotopic neuroblastoma mouse model, discovering an impressive inhibition of tumor growth and indicating good chances for the use of Roniciclib in vivo. We demonstrated that Roniciclib is not only a Wnt/β-catenin signaling inhibitor, but also a nucleolar stress inducer, revealing a possible novel mechanism underlying Roniciclib-mediated repression of cell proliferation. Furthermore, we found that high expression of Nucleophosmin-1 correlates with patients' short survival. The co-expression of several stem cell surface antigens such as CD44v6 and CD114, together with the nucleolar markers here described, extends new possibilities to isolate undifferentiated subpopulations from neuroblastoma and identify new targets for the treatment of this childhood malignancy. Neuroblastoma (NB) is an embryonic pediatric tumor that originates from neural crest progenitors cells 1,2. NB is the most common tumor in young children, about the 90% of cases happen in children less than 5 years old 3. NB is characterized by clinical, biologic and genomic remarkable heterogeneity that affected the survival of NB patients despite intensive therapy 4,5. Cancer stem cells (CSCs) are suggested to be responsible for drug resistance and relapse due to their ability to self-renew, and to differentiate into heterogeneous lineages of cancer cells 6. Heterogeneity within a given cancer arises from diverse cell types recruited to the tumor, and from genetic or epigenetic differences among the cancer cells themselves 7,8. CSCs are the exclusive sources of all tumor cells, survive and persist after cancer therapy and are responsible for tumor relapse and metastasis 9. The concept of CSCs has immediate therapeutic consequences: if cancer growth is sustained by CSCs, then curative therapy will require targeting of this specific sub-population 10. The clinical presentation and the treatment response of advanced NB, which results in relapse and a refractory state after a good response to the initial chemotherapy, suggests the possibility that CSCs exist in NB tumors 11. Moreover, the heterogeneity of NB tumor histology and biology may suggest the existence of selfrenewing multipotent CSCs 12. NB tumors with unfavorable prognosis have been shown to contain a population of undifferentiated stem cells responsible for their malignant state 13. Putative CSCs identification in prima...

show abstract

The nucleolus fine-tunes the orchestration of an early neuroprotection response in neurodegeneration

Cited by 9 publications

References 21 publications

Kinase Signalling in Huntington's Disease

Kinase Signalling in Huntington's Disease

The involvement of tau in nucleolar transcription and the stress response

Roniciclib down-regulates stemness and inhibits cell growth by inducing nucleolar stress in neuroblastoma

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