scholarly journals The coordinate actions of calcineurin and Hog1 mediate the response to cellular stress through multiple nodes of the cell cycle network

2019 ◽  
Author(s):  
Cassandra M. Leech ◽  
Mackenzie J. Flynn ◽  
Heather E. Arsenault ◽  
Jianhong Ou ◽  
Haibo Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Regulatory Network ◽  
Adaptive Response ◽  
Environmental Stressors ◽  
Adaptive Responses ◽  
Cycle Arrest ◽  
Response To Stress ◽  
Stress Signals

SummaryUpon exposure to environmental stressors, cells transiently arrest the cell cycle while they adapt and restore homeostasis. A challenge for all cells is to distinguish between diverse stress signals and coordinate the appropriate adaptive response with cell cycle arrest. Here we investigate the role of the stress-activated phosphatase calcineurin (CN) in this process and show that CN utilizes multiple pathways to control the cell cycle. Upon activation, CN inhibits transcription factors (TFs) that regulate the G1/S transition through activation of the stress-activated MAPK Hog1. In contrast, CN inactivates G2/M TFs through a combination of Hog1-dependent and -independent mechanisms. These findings demonstrate that CN and Hog1 act in a coordinated manner at multiple nodes of the cell cycle-regulatory network to rewire gene expression and arrest cells in response to stress. Our results suggest that crosstalk between CN and stress-activated MAPKs helps cells tailor their adaptive responses to specific stressors.

scholarly journals noxin, a Novel Stress-Induced Gene Involved in Cell Cycle and Apoptosis

2007 ◽  
Vol 27 (15) ◽  
pp. 5430-5444 ◽  
Author(s):  
Naoki Nakaya ◽  
Jill Hemish ◽  
Peter Krasnov ◽  
Sang-Yong Kim ◽  
Yuri Stasiv ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Localization Signals ◽  
Protein Levels ◽  
Cell Defense ◽  
Cycle Arrest ◽  
Wide Range ◽  
Dependent Protein ◽  
Response To Stress ◽  
Stress Signals ◽  
Inducible Gene

ABSTRACT We describe a novel stress-induced gene, noxin, and a knockout mouse line with an inactivated noxin gene. The noxin gene does not have sequelogs in the genome and encodes a highly serine-rich protein with predicted phosphorylation sites for ATM, Akt, and DNA-dependent protein kinase kinases; nuclear localization signals; and a Zn finger domain. noxin mRNA and protein levels are under tight control by the cell cycle. noxin, identified as a nitric oxide-inducible gene, is strongly induced by a wide range of stress signals: γ- and UV irradiation, hydrogen peroxide, adriamycin, and cytokines. This induction is dependent on p53. Noxin accumulates in the nucleus in response to stress and, when ectopically expressed, Noxin arrests the cell cycle at G1; although it also induces p53, the cell cycle arrest function of Noxin is independent of p53 activity. noxin knockout mice are viable and fertile; however, they have an enlarged heart, several altered hematopoietic parameters, and a decreased number of spermatids. Importantly, loss or downregulation of Noxin leads to increased cell death. Our results suggest that Noxin may be a component of the cell defense system: it is activated by various stress stimuli, helps cells to withdraw from cycling, and opposes apoptosis.

scholarly journals Yeast replicative aging leads to permanent cell cycle arrest in G1 effectuated by the start repressor Whi5

2018 ◽  
Author(s):  
Jing Yang ◽  
Ziwei Wang ◽  
Xili Liu ◽  
Hao Li ◽  
Qi Ouyang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Microfluidic Devices ◽  
Replicative Aging ◽  
Cycle Arrest ◽  
Permanent Cell ◽  
Response To Stress ◽  
Stress Signals ◽  
Mother Cells ◽  
Major Mediator

AbstractYeast replicative aging has been a canonical model for aging research. Since replicative aging eventually leads to permanent cell cycle arrest, a fundamental question is how cells sense the signals from aging and communicate that to the cell cycle control machineries. Using microfluidic devices to track individual mother cells labeled by two different cell cycle markers Whi5-tdTomato and Myo1-EGFP, we measured the length of different cell cycle phases as a function of age and the distribution of cell death in different cell cycle phases. We found that the majority of the cells died in the G1 phase, and their G1 cell cycle length increased drastically in the last few cell divisions. This increase of G1 length correlates with the increase of the nuclear concentration of Whi5, which is a major transcriptional suppressor of the cell cycle start check point. Interestingly, this correlation is apparent only above a threshold concentration of Whi5. We show that in response to external stress, Whi5 concentration increases and cell growth slows down in a Whi5 dependent manner, and that Whi5 deletion significantly extends the lifespan. Together these data suggest the existence of a programmed control to arrest cell cycle in G1 in response to stress signals due to aging, and that Whi5 is a major mediator of this process. Our findings may have important implications in understanding senescence and cancer in mammalian cells, which have a parallel G1/S control system with Rb (a well known tumor suppressor) as the analog of Whi5.Significance statementIn this work, we used microfluidic devices to track individual mother cells labeled by two cell cycle markers Whi5-tdTomato and Myo1-EGFP. We found that aging leads to significant lengthening of G1 phase in old cells and the eventual permanent cell cycle arrest in G1, and Whi5 plays an important role in implementing such a program. We show that oxidative stress can lead to the increase of Whi5 expression and the slow-down of cell division. Furthermore, Whi5 deletion significantly extends the lifespan. The result suggest the existence of a programmed control to arrest cell cycle in G1 in response to stress signals due to aging, and that Whi5 is a major mediator of this process.

scholarly journals Phytohormones, Isoprenoids, and Role of the Apicoplast in Recovery from Dihydroartemisinin-Induced Dormancy of Plasmodium falciparum

2018 ◽  
Vol 62 (3) ◽  
Author(s):  
Marvin Duvalsaint ◽  
Dennis E. Kyle
Keyword(s):  
Cell Cycle ◽  
Plasmodium Falciparum ◽  
Abscisic Acid ◽  
Stress Response ◽  
Regulatory Network ◽  
Dormancy Release ◽  
Content Type ◽  
Cycle Arrest ◽  
Aba Synthesis

ABSTRACT Many organisms undergo dormancy as a stress response to survive under unfavorable conditions that might impede development. This is observed in seeds and buds of plants and has been proposed as a mechanism of drug evasion and resistance formation in Plasmodium falciparum . We explored the effects of the phytohormones abscisic acid (ABA) and gibberellic acid (GA) on dihydroartemisinin (DHA)-induced dormant erythrocytic stages of P. falciparum parasites. Dormant ring stages exposed to ABA and GA recovered from dormancy up to 48 h earlier than parasites exposed to DHA alone. Conversely, fluridone, an herbicide inhibitor of ABA synthesis, blocked emergence from dormancy. Additionally, the role of the apicoplast was assessed in dormant parasite recovery. Apicoplast-deficient P. falciparum remained viable for up to 8 days without the organelle and recrudesced only when supplemented with isopentyl pyrophosphate (IPP). IPP was not required for survival in the dormant state. Fosmidomycin inhibition of isoprenoid biosynthesis did not prevent dormancy release from occurring in parasites with an intact apicoplast, but IPP or geranylgeranyl pyrophosphate was needed for complete recrudescence. In addition, the apicoplast and specifically the isoprenoids it produces are essential for recovery of dormant parasites. In summary, ABA and GA have significant effects on dormant parasites, and the phenotypes produced by these phytohormones and the herbicide fluridone also provide a means to explore the mechanism(s) underlying dormancy and the regulatory network that promotes cell cycle arrest in P. falciparum .

scholarly journals Role of Mis Localization of DNA Repair Factors in Cell Cycle Arrest

2019 ◽  
Vol 116 (3) ◽  
pp. 76a
Author(s):  
Manasvita Vashisth ◽  
Sangkyun Cho ◽  
Dennis Discher
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Cell Cycle Arrest ◽  
Cycle Arrest

scholarly journals Arsenic hexoxide has differential effects on cell proliferation and genome-wide gene expression in human primary mammary epithelial and MCF7 cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donguk Kim ◽  
Na Yeon Park ◽  
Keunsoo Kang ◽  
Stuart K. Calderwood ◽  
Dong-Hyung Cho ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Mammary Epithelial ◽  
Mcf7 Cells ◽  
Differential Effects ◽  
Cycle Arrest ◽  
Genome Wide ◽  
Human Mammary Epithelial ◽  
Genome Wide Gene Expression

AbstractArsenic is reportedly a biphasic inorganic compound for its toxicity and anticancer effects in humans. Recent studies have shown that certain arsenic compounds including arsenic hexoxide (AS4O6; hereafter, AS6) induce programmed cell death and cell cycle arrest in human cancer cells and murine cancer models. However, the mechanisms by which AS6 suppresses cancer cells are incompletely understood. In this study, we report the mechanisms of AS6 through transcriptome analyses. In particular, the cytotoxicity and global gene expression regulation by AS6 were compared in human normal and cancer breast epithelial cells. Using RNA-sequencing and bioinformatics analyses, differentially expressed genes in significantly affected biological pathways in these cell types were validated by real-time quantitative polymerase chain reaction and immunoblotting assays. Our data show markedly differential effects of AS6 on cytotoxicity and gene expression in human mammary epithelial normal cells (HUMEC) and Michigan Cancer Foundation 7 (MCF7), a human mammary epithelial cancer cell line. AS6 selectively arrests cell growth and induces cell death in MCF7 cells without affecting the growth of HUMEC in a dose-dependent manner. AS6 alters the transcription of a large number of genes in MCF7 cells, but much fewer genes in HUMEC. Importantly, we found that the cell proliferation, cell cycle, and DNA repair pathways are significantly suppressed whereas cellular stress response and apoptotic pathways increase in AS6-treated MCF7 cells. Together, we provide the first evidence of differential effects of AS6 on normal and cancerous breast epithelial cells, suggesting that AS6 at moderate concentrations induces cell cycle arrest and apoptosis through modulating genome-wide gene expression, leading to compromised DNA repair and increased genome instability selectively in human breast cancer cells.

Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after 131I, γ Radiation and H2O2

2019 ◽  
Vol 105 (3) ◽  
pp. 839-853
Author(s):  
Aglaia Kyrilli ◽  
David Gacquer ◽  
Vincent Detours ◽  
Anne Lefort ◽  
Frédéric Libert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Iodide Uptake ◽  
Transcriptomic Response ◽  
Uptake Inhibition ◽  
Γ Radiation ◽  
Damage Response

Abstract Background The early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-induced DNA damage response and gene expression in primary cultured human thyrocytes. Methods Following exposure of thyrocytes, in the presence or absence of TSH, to 131I (β radiation), γ radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response. Results Overall, the thyrocyte responses following exposure to β or γ radiation and to H2O2 were similar. However, TSH increased 131I-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after 131I exposure. Conclusions TSH specifically increased 131I-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to 131I.

scholarly journals Iodide- and Glucose-Handling Gene Expression Regulated by Sorafenib or Cabozantinib in Papillary Thyroid Cancer

2015 ◽  
Vol 100 (5) ◽  
pp. 1771-1779 ◽  
Author(s):  
Maomei Ruan ◽  
Min Liu ◽  
Qianggang Dong ◽  
Libo Chen
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Signal Transduction ◽  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Western Blot ◽  
Glucose Transporter ◽  
Signal Transduction Pathways ◽  
Papillary Thyroid ◽  
Cycle Arrest

Abstract Context: The aberrant silencing of iodide-handling genes accompanied by up-regulation of glucose metabolism presents a major challenge for radioiodine treatment of papillary thyroid cancer (PTC). Objective: This study aimed to evaluate the effect of tyrosine kinase inhibitors on iodide-handling and glucose-handling gene expression in BHP 2-7 cells harboring RET/PTC1 rearrangement. Main Outcome Measures: In this in vitro study, the effects of sorafenib or cabozantinib on cell growth, cycles, and apoptosis were investigated by cell proliferation assay, cell cycle analysis, and Annexin V-FITC apoptosis assay, respectively. The effect of both agents on signal transduction pathways was evaluated using the Western blot. Quantitative real-time PCR, Western blot, immunofluorescence, and radioisotope uptake assays were used to assess iodide-handling and glucose-handling gene expression. Results: Both compounds inhibited cell proliferation in a time-dependent and dose-dependent manner and caused cell cycle arrest in the G0/G1 phase. Sorafenib blocked RET, AKT, and ERK1/2 phosphorylation, whereas cabozantinib blocked RET and AKT phosphorylation. The restoration of iodide-handling gene expression and inhibition of glucose transporter 1 and 3 expression could be induced by either drug. The robust expression of sodium/iodide symporter induced by either agent was confirmed, and 125I uptake was correspondingly enhanced. 18F-fluorodeoxyglucose accumulation was significantly decreased after treatment by either sorafenib or cabozantinib. Conclusions: Sorafenib and cabozantinib had marked effects on cell proliferation, cell cycle arrest, and signal transduction pathways in PTC cells harboring RET/PTC1 rearrangement. Both agents could be potentially used to enhance the expression of iodide-handling genes and inhibit the expression of glucose transporter genes.

scholarly journals Cellular Senescence in Liver Disease and Regeneration

2021 ◽  
Author(s):  
Sofia Ferreira-Gonzalez ◽  
Daniel Rodrigo-Torres ◽  
Victoria L. Gadd ◽  
Stuart J. Forbes
Keyword(s):  
Cell Cycle ◽  
Liver Disease ◽  
Cell Cycle Arrest ◽  
Genomic Instability ◽  
Cellular Senescence ◽  
Cell Populations ◽  
Cycle Arrest ◽  
Relevant Role ◽  
Extent Of Damage

AbstractCellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

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