RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels

The RNA exosome is a ubiquitously expressed complex of nine core proteins (EXOSC1-9) and associated nucleases responsible for RNA processing and degradation. Mutations in EXOSC3, EXOSC8, EXOSC9, and the exosome cofactor RBM7 cause pontocerebellar hypoplasia and motor neuronopathy. We investigated the consequences of exosome mutations on RNA metabolism and cellular survival in zebrafish and human cell models. We observed that levels of mRNAs encoding p53 and ribosome biogenesis factors are increased in zebrafish lines with homozygous mutations of exosc8 or exosc9, respectively. Consistent with higher p53 levels, mutant zebrafish have a reduced head size, smaller brain, and cerebellum caused by an increased number of apoptotic cells during development. Down-regulation of EXOSC8 and EXOSC9 in human cells leads to p53 protein stabilisation and G2/M cell cycle arrest. Increased p53 transcript levels were also observed in muscle samples from patients with EXOSC9 mutations. Our work provides explanation for the pathogenesis of exosome-related disorders and highlights the link between exosome function, ribosome biogenesis, and p53-dependent signalling. We suggest that exosome-related disorders could be classified as ribosomopathies.

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Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Cancers ◽

10.3390/cancers13081790 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1790

Author(s):

Katarzyna Malarz ◽

Jacek Mularski ◽

Michał Kuczak ◽

Anna Mrozek-Wilczkiewicz ◽

Robert Musiol

Keyword(s):

Cell Cycle ◽

Anticancer Activity ◽

Cell Cycle Arrest ◽

Anticancer Agents ◽

Kinase Inhibitors ◽

P53 Protein ◽

Structural Similarity ◽

M Cell ◽

Cycle Arrest ◽

Small Series

Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as convenient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Although the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and GADD44. Other proteins such as cdc2 were also expressed at a higher level. Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

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Radiation could induce p53-independent and cell cycle - unrelated apoptosis in 5-fluorouracil radiosensitized head and neck carcinoma cells

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-069 ◽

2002 ◽

Vol 80 (7) ◽

pp. 638-643 ◽

Cited By ~ 11

Author(s):

C Didelot ◽

J F Mirjolet ◽

M Barberi-Heyob ◽

C Ramacci ◽

J L Merlin

Keyword(s):

Cell Cycle ◽

Protein Expression ◽

Cell Cycle Arrest ◽

Cell Line ◽

P53 Protein ◽

Apoptosis Induction ◽

M Cell ◽

Cycle Arrest ◽

P53 Protein Expression ◽

Intrinsic Radiosensitivity

The effect of chemoresistance induction in radiosensitivity and cellular behavior after irradiation remains misunderstood. This study was designed to understand the relationship between radiation-induced cell cycle arrest, apoptosis, and radiosensitivity in KB cell line and KB3 subline selected after 5-fluorouracil (5FU) exposure. Exposure of KB cells to 5FU led to an increase in radiosensitivity. G2/M cell cycle arrest was observed in the two cell lines after irradiation. The radioresistant KB cell line reached the maximum arrest two hours before KB3. The cellular exit from this arrest was found to be related to the wild type p53 protein expression induction. After irradiation, only KB3 cell line underwent apoptosis. This apoptosis induction seemed to be independent of G2/M arrest exit, which was carried out later. The difference in radiosensitivity between KB and KB3 subline may result therefore from both a difference in apoptosis induction and a difference in G2/M arrest maximum duration. Moreover, 5FU exposure has led to an increase in constitutive p53 protein expression, which may be associated with an increase in basal apoptosis cell fraction. Given the existing correlation between radiosensitivity and the percentage of basal apoptosis, the constitutive p53 protein expression may be related to intrinsic radiosensitivity in our cellular model.Key words: cellular radiosensitivity, G2/M arrest, p53, apoptosis.

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Involvement of G2/M Cell Cycle Arrest and the Mitochondrial Pathway in Boletopsis leucomelaena (Pers.) Fayod (Agaricomycetideae) Lectin-Induced Apoptosis of Human Leukemia U937 Cells

International Journal of Medicinal Mushrooms ◽

10.1615/intjmedmushr.v7.i12.190 ◽

2005 ◽

Vol 7 (1-2) ◽

pp. 201-212 ◽

Cited By ~ 3

Author(s):

Yu Koyama ◽

Takuji Suzuki ◽

Akane Kajiya ◽

Mamoru Isemura

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Mitochondrial Pathway ◽

Human Leukemia ◽

U937 Cells ◽

M Cell ◽

Cycle Arrest ◽

Induced Apoptosis

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Exploring a Link Between NF-kappaB and G2/M Cell Cycle Arrest in Breast Cancer Cells

10.21236/ada425730 ◽

2004 ◽

Author(s):

Shelly M. Davis

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Breast Cancer Cells ◽

M Cell ◽

Cycle Arrest ◽

Nf Kappab

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Exploring a Link Between NF-KB and G2/M Cell Cycle Arrest in Breast Cancer Cells

10.21236/ada436875 ◽

2005 ◽

Author(s):

Shelly M. Davis ◽

Shigeki Miyamoto

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Breast Cancer Cells ◽

M Cell ◽

Cycle Arrest

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Pisosterol Induces G2/M Cell Cycle Arrest and Apoptosis via the ATM/ATR Signaling Pathway in Human Glioma Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200203160117 ◽

2020 ◽

Vol 20 (6) ◽

pp. 734-750

Author(s):

Wallax A.S. Ferreira ◽

Rommel R. Burbano ◽

Claudia do Ó. Pessoa ◽

Maria L. Harada ◽

Bárbara do Nascimento Borges ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Signaling Pathway ◽

Glioma Cell ◽

Molecular Mechanisms ◽

Glioma Cells ◽

Dependent Manner ◽

M Cell ◽

Trypan Blue Exclusion ◽

Cycle Arrest

Background: Pisosterol, a triterpene derived from Pisolithus tinctorius, exhibits potential antitumor activity in various malignancies. However, the molecular mechanisms that mediate the pisosterol-specific effects on glioma cells remain unknown. Objective: This study aimed to evaluate the antitumoral effects of pisosterol on glioma cell lines. Methods: The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue exclusion assays were used to evaluate the effect of pisosterol on cell proliferation and viability in glioma cells. The effect of pisosterol on the distribution of the cells in the cell cycle was performed by flow cytometry. The expression and methylation pattern of the promoter region of MYC, ATM, BCL2, BMI1, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, MDM2, p14ARF and TP53 was analyzed by RT-qPCR, western blotting and bisulfite sequencing PCR (BSP-PCR). Results: Here, it has been reported that pisosterol markedly induced G2/M arrest and apoptosis and decreased the cell viability and proliferation potential of glioma cells in a dose-dependent manner by increasing the expression of ATM, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, p14ARF and TP53 and decreasing the expression of MYC, BCL2, BMI1 and MDM2. Pisosterol also triggered both caspase-independent and caspase-dependent apoptotic pathways by regulating the expression of Bcl-2 and activating caspase-3 and p53. Conclusions: It has been, for the first time, confirmed that the ATM/ATR signaling pathway is a critical mechanism for G2/M arrest in pisosterol-induced glioma cell cycle arrest and suggests that this compound might be a promising anticancer candidate for further investigation.

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Deglucohellebrin: A Potent Agent for Glioblastoma Treatment

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666191121110848 ◽

2020 ◽

Vol 20 (1) ◽

pp. 103-110

Author(s):

Evrysthenis Vartholomatos ◽

George A. Alexiou ◽

Georgios S. Markopoulos ◽

Diamanto Lazari ◽

Olga Tsiftsoglou ◽

...

Keyword(s):

Anticancer Agents ◽

Primary Brain Tumor ◽

Behavioral Alterations ◽

Endemic Plant ◽

M Cell ◽

Apoptotic Pathway ◽

Cycle Arrest ◽

Dismal Prognosis ◽

Mitochondrial Membrane Depolarization ◽

Induced Changes

Background: Glioblastoma is the most common primary brain tumor in adults with a dismal prognosis. To date, several anticancer agents have been isolated from plants. Helleborus odorus subsp. Cyclophyllus is an endemic plant of the Balcan flora. Herewith, we investigated for the first time, the anti-glioma effect of deglucohellebrin (DGH) extracted from the roots of Helleborus. Methods: We investigated the effect of DGH in U251MG, T98G and U87G glioblastoma cell lines. We selected the T98G cells because of their inherent temozolomide resistance. Results: The IC50 value of reduced viability for DGH was 7x10-5M in U251MG cells, 5x10-5M for the T98G cells and 4x10-5M in U87G cells during 72h treatment. DGH induced G2/M cell cycle arrest, caspace-8 activation and significant mitochondrial membrane depolarization, suggesting the activation of the intrinsic, mitochondrial- dependent apoptotic pathway. DGH and temozolomide induced changes in CDs’ expression in U251MG and T98G cells. In zebrafish, DGH did not induce toxicity or behavioral alterations. Conclusion: The present study is the first to determine the anti-glioma activity of DGH. DGH may be a potent agent for glioblastoma treatment and further studies are needed.

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Mechanisms of Nuclear Transport in the cell: RNA exosome in Saccharomyces cerevisiae

Bionatura ◽

10.21931/rb/2020.05.04.25 ◽

2020 ◽

Vol 5 (4) ◽

pp. 1423-1426

Author(s):

Bruna Rech ◽

Fernando A. Gonzales-Zubiate

Keyword(s):

Saccharomyces Cerevisiae ◽

Catalytic Activity ◽

Rna Processing ◽

Cellular Localization ◽

Nuclear Transport ◽

Single Units ◽

Yeast Saccharomyces Cerevisiae ◽

Rna Transcripts ◽

Non Coding Rnas ◽

Rna Exosome

Ribonucleases (RNases) functions in the cell include precise maturation of non- coding RNAs and degradation of specific RNA transcripts that are no longer necessary. RNAses are present in the cell as single units or assembled as multimeric complexes; one of these complexes is the RNA exosome, a highly conserved complex essential for RNA processing and degradation. In the yeast Saccharomyces cerevisiae, the RNA exosome comprises eleven subunits, two with catalytic activity: Rrp6 and Rrp44, where the Rrp6 subunit is exclusively nuclear. Despite the RNA exosome has been intensively investigated since its discovery in 1997, only a few studies were accomplished concerning its nuclear transport. This review describes recent research about cellular localization and transport of this essential complex.

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