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Publications (85)
The modulation of autophagy plays a dual role in tumor cells, with the potential to both promote and suppress tumor proliferation. In order to gain a deeper understanding of the nature of autophagy, we have developed a chemical reaction kinetic model of autophagy and apoptosis based on the mass action kinetic models that have been previously descri...
Dynamic regulation of the cellular proteome is mainly controlled in the endoplasmic reticulum (ER). Accumulation of misfolded proteins due to ER stress leads to the activation of unfolded protein response (UPR). The primary role of UPR is to reduce the bulk of damages and try to drive back the system to the former or a new homeostatic state by auto...
The endoplasmic reticulum (ER) plays a crucial role in cellular homeostasis. When ER stress is generated, an autophagic self-digestive process is activated to promote cell survival; however, cell death is induced in the case of excessive levels of ER stress. The aim of the present study was to investigate the effect of a natural compound called sul...
Macroautophagy/autophagy is a highly-conserved catabolic process eliminating dysfunctional cellular components and invading pathogens. Autophagy malfunction contributes to disorders such as cancer, neurodegenerative and inflammatory diseases. Understanding autophagy regulation in health and disease has been the focus of the last decades. We previou...
One of the main inducers of autophagy-dependent self-cannibalism, called ULK1, is tightly regulated by the two sensor molecules of nutrient conditions and energy status, known as mTOR and AMPK kinases, respectively. Recently, we developed a freely available mathematical model to explore the oscillatory characteristic of the AMPK-mTOR-ULK1 regulator...
Autophagy is a highly-conserved catabolic process eliminating dysfunctional cellular components and invading pathogens. Autophagy malfunction contributes to disorders such as cancer, neurodegenerative and inflammatory diseases. Understanding autophagy regulation in health and disease has been the focus of the last decades. We previously provided an...
The circadian clock governs rhythmic cellular functions by driving the expression of a substantial fraction of the genome and thereby significantly contributes to the adaptation to changing environmental conditions. Using the circadian model organism Neurospora crassa, we show that molecular timekeeping is robust even under severe limitation of car...
Autophagy-dependent cellular survival is tightly regulated by both kinases and phosphatases. While mTORC1 inhibits autophagy by phosphorylating ULK1, PP2A is able to remove this phosphate group from ULK1 and promotes the key inducer of autophagosome formation. However, ULK1 inhibits mTORC1, mTORC1 is able to down-regulate PP2A. In addition, the act...
Endoplasmic reticulum stress-dependent accumulation of incorrectly folded proteins leads to activation of the unfolded protein response. The role of the UPR is to avoid cell damage and restore the homeostatic state by autophagy; however, excessive ER stress results in apoptosis. Here, we investigated the ER stress-dependent feedback loops inside on...
We describe a precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to determine the mechanisms by which SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 378 UC patients we map the regulator...
The COVID-19 pandemic caused by SARS-CoV-2 has resulted in an urgent need for identifying potential therapeutic drugs. In the first half of 2020 tropic antimalarial drugs, such as chloroquine (CQ) or hydroxochloroquine (HCQ) were the focus of tremendous public attention. In the initial periods of the pandemic, many scientific results pointed out th...
The Warburg effect has been considered a potential therapeutic target to fight against cancer progression. In KRAS mutant cells, PKM2 (pyruvate kinase isozyme M2) is hyper-activated, and it induces GLUT1 expression; therefore, KRAS has been closely involved in the initiation of Warburg metabolism. Although mTOR (mammalian target of rapamycin), a we...
Although autophagy is a type of programmed cell death, it is also essential for cell survival upon tolerable level of various stress events. For the cell to respond adequately to an external and/or internal stimulus induced by cellular stress, autophagy must be controlled in a highly regulated manner. By using systems biology techniques, here we ex...
Autophagy is an intracellular digestive process, which has a crucial role in maintaining cellular homeostasis by self-eating the unnecessary and/or damaged components of the cell at various stress events. ULK1, one of the key elements of autophagy activator complex, together with the two sensors of nutrient and energy conditions, called mTORC1 and...
Significance:
Persistent oxidative stress is a common feature of cancer cells, giving a specific weapon to selectively eliminate them. Ascorbate in pharmacologic concentration can contribute to the suspended formation of hydroxyl radical via the Fenton reaction, thus it can be an important element of the oxidative stress therapy against cancer cel...
Scientific results have revealed that autophagy is able to promote cell survival in response to endoplasmic reticulum (ER) stress while drastic events result in apoptotic cell death. Here, we analyse the important crosstalk of life‐and‐death decisions from a systems biological perspective by studying the regulatory modules of the unfolded protein r...
Cellular homeostasis is controlled by an evolutionary conserved cellular digestive process called autophagy. This mechanism is tightly regulated by the two sensor elements called mTORC1 and AMPK. mTORC1 is one of the master regulators of proteostasis, while AMPK maintains cellular energy homeostasis. AMPK is able to promote autophagy by phosphoryla...
We describe a novel precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to identify the exact mechanisms of how SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 377 UC patients, we mapped...
Oxidative stress results in activation of several signal transduction pathways controlled by the PERK-substrate NRF2 (nuclear factor erythroid 2-related factor 2); meanwhile the ongoing cell division cycle has to be blocked. It has been recently shown that Cyclin D1 got immediately down-regulated via PERK pathway in response to oxidative stress lea...
Pharmacologic ascorbate induced cell death and ferroptosis share common features such as iron dependency, production of ROS, lipid peroxidation, caspase independency and the possible involvement of autophagy. These observations lead us to hypothesize that ferroptosis may also be involved in cancer cell death due to pharmacologic ascorbate treatment...
NF‐E2‐related factor 2 (NRF2) transcription factor has a fundamental role in cell homeostasis maintenance as one of the master regulators of oxidative and electrophilic stress responses. Previous studies have shown that a regulatory connection exists between NRF2 and autophagy during reactive oxygen species‐generated oxidative stress. The aim of th...
Although the primary role of autophagy-dependent cellular self-eating is cytoprotective upon various stress events (such as starvation, oxidative stress, and high temperatures), sustained autophagy might lead to cell death. A transcription factor called NRF2 (nuclear factor erythroid-related factor 2) seems to be essential in maintaining cellular h...
Ostreococcus tauri is the smallest free-living unicellular organism with one copy of each core cell cycle genes in its genome. There is a growing interest in this green algae due to its evolutionary origin. Since O. tauri is diverged early in the green lineage, relatively close to the ancestral eukaryotic cell, it might hold a key phylogenetic posi...
The maintenance of cellular homeostasis is largely dependent on the ability of cells to give an adequate response to various internal and external stimuli. We have recently proposed that the life-and-death decision in endoplasmic reticulum (ER) stress response is defined by a crosstalk between autophagy, apoptosis, and mTOR-AMPK pathways, where the...
Figure S1: EGCG induces autophagy in a concentration-dependent manner. Figure S2: the effect of H-89 treatment on cell viability. Figure S3: mTOR pathway is essential for EGCG-dependent autophagy induction. Figure S4: EGCG pretreatment extends autophagy-dependent survival with respect to TG-induced ER stress. Figure S5: EGCG pretreatment extends au...
In response to developmental and environmental conditions, cells exit the mitotic cell cycle and enter the meiosis program to generate haploid gametes from diploid germ cells. Once cells decide to enter the meiosis program they become irreversibly committed to the completion of meiosis irrespective of the presence of cue signals. How meiotic entry...
Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER) leads to the activation of three branches (Protein kinase (RNA)-like endoplasmic reticulum kinase [PERK], Inositol requiring protein 1 [IRE-1] and Activating trascription factor 6 [ATF6], respectively) of unfolded protein response (UPR). The primary role of UPR is to try...
Time course profile of cell viability, autophagy and apoptosis in TG-induced ER stress when autophagy was activated.
HEK293T cells were pre-treated with rapamycin (100 nM for two hours) followed by TG addition (10 μM for two hours). A) The relative cell viability after TG treatment was denoted in time. B) Densitometry data represent the intensity o...
Time course profile of cell viability, autophagy and apoptosis in TG-induced ER stress when both GADD34 and mTOR was inhibited.
HEK293T cells were pre-treated with GB (5 μM for one hour) then with rapamycin (100 nM for two hours) followed by TG addition (10 μM for two hours). The GB level was kept high until end of the cell treatment. A) The relati...
Testing the effect of GADD34 silencing with respect to ER stress.
GADD34 was silenced in HEK293T cells, then cells were treated with 10 μM TG for two hours and pre-treated with resveratrol (10 μM for twenty-four hours) followed by TG addition (10 μM for two hours). The successful GADD34 silencing was demonstrated both by A) real-time PCR and B) Wes...
Time course profile of cell viability, autophagy and apoptosis in TG-induced ER stress.
HEK293T cells were treated with TG (10 μM for two hours). A) The relative cell viability after TG treatment was denoted in time. B) Densitometry data represent the intensity of proCaspase-3, cleaved PARP, GADD34 normalised for GAPDH, LC3II normalized for LC3I, U...
The effect of GADD34 inhibition with respect to ER stress using another ER stressor.
HEK293T cells were pre-treated with GB (5 μM for one hour) followed by TM addition (100 μM for two hours). The GB level was kept high until end of the cell treatment. A) The relative number of viable cell was denoted in time after TM treatment. B) The autophagy (LC...
Time course profile of cell viability, autophagy and apoptosis in TG-induced ER stress when GADD34 inhibition is combined with resveratrol addition.
HEK293T cells were pre-treated with GB (5 μM for one hours) then with resveratrol (10 μM for twenty-four hours) followed by TG addition (10 μM for two hours). The GB level was kept high until end of th...
The balance of protein synthesis and proteolysis (i.e. proteostasis) is maintained by a complex regulatory network in which mTOR (mechanistic target of rapamycin serine/threonine kinase) pathway and unfolded protein response are prominent positive and negative actors. The interplay between the two systems has been revealed; however the mechanistic...
The effect of the GADD34 inhibitor guanabenz (GB) on cell viability in TG-induced ER stress.
HEK293T cells were treated with various concentration of GB for one hour. The relative cell viability after GB treatment was denoted (error bars represent standard deviation, asterisks indicate statistically significant difference from the control: ∗—p < 0....
Time course profile of cell viability, autophagy and apoptosis in TG-induced ER stress when GADD34 was inhibited.
HEK293T cells were pre-treated with GB (5 μM for one hour) followed by TG addition (10 μM for two hours). The GB level was kept high until end of the cell treatment. A) The relative cell viability after TG treatment was denoted in time....
Time course profile of cell viability, autophagy and apoptosis in TG-induced ER stress with/without addition of autophagy inhibitor.
HEK293T cells were pre-treated with 3-MA (1 mM for two hours) followed by TG addition (10 μM for two hours). A) The relative cell viability after TG treatment was denoted in time. B) Densitometry data represent the in...
Analysing autophagy activation in the presence of an autophagic flux inhibitor.
HEK293T cells were pre-treated without/with Bafilomycin A (100 nM Baf for two hours) followed by rapamycin (100 nM for two hours), 3-MA (1 mM for two hours) or TG (10 μM for 30 mins) addition. The Rap and 3-MA treatment was combined with TG (10 μM for 30 mins). A) The r...
The effect of GADD34 inhibition with respect to ER stress using another cell line.
HepG2 cells were pre-treated with GB (5 μM for one hour) followed by TG addition (25 μM for two hours). The GB level was kept high until end of the cell treatment. A) The relative number of viable cell was denoted in time after TG treatment. B) The autophagy (LC3), t...
Time course profile of cell viability, autophagy and apoptosis in TG-induced ER stress when autophagy was hyper-activated by resveratrol.
HEK293T cells were pre-treated with resveratrol (10 μM for twenty-four hours) followed by TG addition (10 μM for two hours). A) The relative cell viability after TG treatment was denoted in time. B) Densitometry...
One of the most important tasks of a living organism is to maintain its genetic integrity with respect to stress. Endoplasmic reticulum (ER) has a crucial role in sensing cellular homeostasis by controlling metabolism, proteostasis, and several signaling processes. ER stressors can induce autophagy-dependent survival; however excessive level of str...
Supplementary Material contains a detailed description about the stochastic model used for supporting the experimental data by computational simulations. This material also involves the specification of the complete set of elements and parameters of the model and the simulation code is also attached. Second half of the electronic data contains the...
Unfolded or misfolded proteins in the endoplasmic reticulum (ER) trigger an adaptive ER stress response known as unfolded protein response (UPR). Depending on the severity of ER stress, either autophagy-controlled survival or apoptotic cell death can be induced. The molecular mechanisms by which UPR controls multiple fate decisions have started to...
Each eukaryotic cell of multicellular organisms must be able to maintain its integrity by sensing both external and internal stimuli. The primary goal of the generated response mechanism is to drive back the system to the former or to a new homeostatic state. Moreover, the response has to provide an accurate survival-or-death decision to avoid any...
It has been recently shown that redox imbalance of luminal pyridine nucleotides in the endoplasmic reticulum (ER) together with oxidative stress results in the activation of autophagy. In the present study we demonstrated that decrease of luminal NADPH/NADP(+) ratio alone by metyrapone was sufficient to promote the mechanism of "self-eating" detect...
Decision-making between life and death is one of the most important tasks of cells to maintain their genetic integrity. While the surviving mechanism is driven by Beclin1-dependent autophagy, the suicide processes are controlled by caspases-mediated apoptosis. Interestingly, both these processes share regulators such as Bcl2 and influence each othe...
Activation of the cyclin-dependent kinase (Cdk1) cyclin B (CycB) complex (Cdk1:CycB) in mitosis brings about a remarkable extent of protein phosphorylation. Cdk1:CycB activation is switch-like, controlled by two auto-amplification loops--Cdk1:CycB activates its activating phosphatase, Cdc25, and inhibits its inhibiting kinase, Wee1. Recent experime...
Supplementary Figures S1–13, Supplementary Tables S1–12
This compressed zipped archive contains plasmid sequence files described below
This compressed zipped archive contains ode model files described below
CellDesigner4.2 file of the gTOW model
Time-lapse microscopic observation of gTOW experiment with mik1+ gene
Cellular systems are generally robust against fluctuations of intracellular parameters such as gene expression level. However, little is known about expression limits of genes required to halt cellular systems. In this study, using the fission yeast Schizosaccharomyces pombe, we developed a genetic 'tug-of-war' (gTOW) method to assess the overexpre...
Bistability of the Cdk1-Wee1-Cdc25 mitotic control network underlies the switch-like transitions between interphase and mitosis. Here, we show by mathematical modeling and experiments in Xenopus egg extracts that protein phosphatase 2A (PP2A), which can dephosphorylate Cdk1 substrates, is essential for this bistability. PP2A inhibition in early int...
The mitotic checkpoint prevents a eukaryotic cell from commencing to separate its replicated genome into two daughter cells (anaphase) until all of its chromosomes are properly aligned on the metaphase plate, with the two copies of each chromosome attached to opposite poles of the mitotic spindle. The mitotic checkpoint is exquisitely sensitive in...
Many aspects of cell physiology are controlled by protein kinases and phosphatases, which together determine the phosphorylation state of targeted substrates. Some of these target proteins are themselves kinases or phosphatases or other components of a regulatory network characterized by feedback and feed-forward loops. In this review we describe s...
Alternation of chromosome replication and segregation is essential for successful completion of the cell cycle and it requires an oscillation of Cdk1 (cyclin-dependent kinase 1)-CycB (cyclin B) activity. In the present review, we illustrate the essential features of checkpoint controlled and uncontrolled cell-cycle oscillations by using mechanical...
Stochastic model for mammalian mitotic exit
This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits distribution and reproduction in any medium, provided the original author and source are credited. Creation of derivativeworks is permitted but the resultingworkmay be distributed only under the same or similar licence to this one....
Repetitive cell cycles, which are essential to the perpetuation of life, are orchestrated by an underlying biochemical reaction network centered around cyclin-dependent protein kinases (Cdks) and their regulatory subunits (cyclins). Oscillations of Cdk1/CycB activity between low and high levels during the cycle trigger DNA replication and mitosis i...
The activity of a protein can be reversibly modulated by post-translational, covalent modifications, such as phosphorylation and dephosphorylation. In many cases, the modulated protein may be phosphorylated by the same kinase on many different amino acid residues. Such multisite phosphorylations may occur progressively (during a single binding even...
The eukaryotic cell cycle comprises an ordered series of events, orchestrated by the activity of cyclin-dependent kinases (Cdks), leading from chromosome replication during S phase to their segregation in mitosis. The unidirectionality of cell-cycle transitions is fundamental for the successful completion of this cycle. It is thought that irrevocab...
The eukaryotic cell cycle requires precise temporal coordination of the activities of hundreds of 'executor' proteins (EPs) involved in cell growth and division. Cyclin-dependent protein kinases (Cdks) play central roles in regulating the production, activation, inactivation and destruction of these EPs. From genome-scale data sets of budding yeast...
The eukaryotic cell cycle requires precise temporal coordination of the activities of hundreds of 'executor' proteins (EPs) involved in cell growth and division. Cyclin-dependent protein kinases (Cdks) play central roles in regulating the production, activation, inactivation and destruction of these EPs. From genome-scale data sets of budding yeast...
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