scholarly journals BAX and SMAC Regulate Bistable Properties of the Apoptotic Caspase System

2019 ◽  
Author(s):  
Stephanie McKenna ◽  
Lucía García-Gutiérrez ◽  
David Matallanas ◽  
Dirk Fey
Keyword(s):  
Cell Line ◽  
Cellular Response ◽  
Current Knowledge ◽  
Cellular Biology ◽  
Caspase Activation ◽  
Activation Threshold ◽  
Bistable Switch ◽  
Bax Protein ◽  
Cell Line Panel ◽  
Biochemical Mechanisms

AbstractThe initiation of apoptosis is a core mechanism in cellular biology by which organisms control the removal of damaged or unnecessary cells. The irreversible activation of caspases is essential for apoptosis, and mathematical models have demonstrated that the process is tightly regulated by positive feedback and a bistable switch. BAX and SMAC are often dysregulated in diseases such as cancer or neurodegeneration and are two key regulators that interact with the caspase system generating the apoptotic switch. Here we present a mathematical model of how BAX and SMAC control the apoptotic switch. Formulated as a system of ordinary differential equations, the model summarises experimental and computational evidence form the literature and incorporates the biochemical mechanisms of how BAX and SMAC interact with the components of the caspase system. Using simulations and bifurcation analysis, we find that both BAX and SMAC regulate the time-delay and activation threshold of the apoptotic switch. Interestingly, the model predicted that BAX (not SMAC) controls the amplitude of the apoptotic switch. Cell culture experiments using siRNA mediated BAX and SMAC knockdowns this model prediction. We further validated the model on data of the NCI-60 cell line panel using BAX protein expression as cell-line specific parameter and show that model simulations correlated with the cellular response to DNA damaging drugs and established a defined threshold for caspase activation that could distinguish between sensitive and resistant melanoma cells. In summary, we present an experimentally validated dynamic model that summarises our current knowledge of how BAX and SMAC regulate the bistable properties of irreversible caspase activation during apoptosis.

scholarly journals BAX and SMAC regulate bistable properties of the apoptotic caspase system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stephanie McKenna ◽  
Lucía García-Gutiérrez ◽  
David Matallanas ◽  
Dirk Fey
Keyword(s):  
Cell Line ◽  
Cellular Response ◽  
Current Knowledge ◽  
Caspase Activation ◽  
Bistable Switch ◽  
Bax Protein ◽  
Cell Line Panel ◽  
A Cell ◽  
Biochemical Mechanisms ◽  
Using Data

AbstractThe initiation of apoptosis is a core mechanism in cellular biology by which organisms control the removal of damaged or unnecessary cells. The irreversible activation of caspases is essential for apoptosis, and mathematical models have demonstrated that the process is tightly regulated by positive feedback and a bistable switch. BAX and SMAC are often dysregulated in diseases such as cancer or neurodegeneration and are two key regulators that interact with the caspase system generating the apoptotic switch. Here we present a mathematical model of how BAX and SMAC control the apoptotic switch. Formulated as a system of ordinary differential equations, the model summarises experimental and computational evidence from the literature and incorporates the biochemical mechanisms of how BAX and SMAC interact with the components of the caspase system. Using simulations and bifurcation analysis, we find that both BAX and SMAC regulate the time-delay and activation threshold of the apoptotic switch. Interestingly, the model predicted that BAX (not SMAC) controls the amplitude of the apoptotic switch. Cell culture experiments using siRNA mediated BAX and SMAC knockdowns validated this model prediction. We further validated the model using data of the NCI-60 cell line panel using BAX protein expression as a cell-line specific parameter and show that model simulations correlated with the cellular response to DNA damaging drugs and established a defined threshold for caspase activation that could distinguish between sensitive and resistant melanoma cells. In summary, we present an experimentally validated dynamic model that summarises our current knowledge of how BAX and SMAC regulate the bistable properties of irreversible caspase activation during apoptosis.

scholarly journals The Occurrence and Biological Activity of Tormentic Acid—A Review

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3797
Author(s):  
Marta Olech ◽  
Wojciech Ziemichód ◽  
Natalia Nowacka-Jechalke
Keyword(s):  
Biological Activity ◽  
Plant Species ◽  
Current Knowledge ◽  
In Vivo Studies ◽  
Natural Sources ◽  
Anti Cancer ◽  
Biochemical Mechanisms ◽  
Tormentic Acid

This review focuses on the natural sources and pharmacological activity of tormentic acid (TA; 2α,3β,19α-trihydroxyurs-2-en-28-oic acid). The current knowledge of its occurrence in various plant species and families is summarized. Biological activity (e.g., anti-inflammatory, antidiabetic, antihyperlipidemic, hepatoprotective, cardioprotective, neuroprotective, anti-cancer, anti-osteoarthritic, antinociceptive, antioxidative, anti-melanogenic, cytotoxic, antimicrobial, and antiparasitic) confirmed in in vitro and in vivo studies is compiled and described. Biochemical mechanisms affected by TA are indicated. Moreover, issues related to the biotechnological methods of production, effective eluents, and TA derivatives are presented.

scholarly journals Detection of antibodies against human platelet antigens 15a and 15b by using a cell line panel

2010 ◽  
Vol 151 (4) ◽  
pp. 402-404 ◽  
Author(s):  
Tomoya Hayashi ◽  
Etsuko Amakishi ◽  
Nobuki Matsuyama ◽  
Kazuta Yasui ◽  
Rika A. Furuta ◽  
...  
Keyword(s):  
Cell Line ◽  
Human Platelet ◽  
Cell Line Panel ◽  
A Cell

scholarly journals Small non-coding RNA transcriptome of the NCI-60 cell line panel

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Erin A. Marshall ◽  
Adam P. Sage ◽  
Kevin W. Ng ◽  
Victor D. Martinez ◽  
Natalie S. Firmino ◽  
...  
Keyword(s):  
Cell Line ◽  
Non Coding Rna ◽  
Cell Line Panel

scholarly journals Ribosome provisioning activates a bistable switch coupled to fast exit from stationary phase

2018 ◽  
Author(s):  
P. Remigi ◽  
G.C. Ferguson ◽  
S. De Monte ◽  
P.B. Rainey
Keyword(s):  
Stationary Phase ◽  
Phenotypic Switch ◽  
Activation Threshold ◽  
Bistable Switch ◽  
Genetic Components ◽  
Colanic Acid ◽  
Stochastic Entry ◽  
Molecular Bases ◽  
Ribosome Biosynthesis ◽  
Selective Regime

AbstractObservations of bacteria at the single-cell level have revealed many instances of phenotypic heterogeneity within otherwise clonal populations, but the selective causes, molecular bases and broader ecological relevance remain poorly understood. In an earlier experiment in which the bacteriumPseudomonas fluorescensSBW25 was propagated under a selective regime that mimicked the host immune response, a genotype evolved that stochastically switched between capsulation states. The genetic cause was a mutation incarBthat decreased the pyrimidine pool (and growth rate), lowering the activation threshold of a pre-existing but hitherto unrecognised phenotypic switch. Genetic components surrounding bifurcation of UTP flux towards DNA/RNA or UDP-glucose (a precursor of colanic acid forming the capsules) were implicated as key components. Extending these molecular analyses – and based on a combination of genetics, transcriptomics, biochemistry and mathematical modelling – we show that pyrimidine limitation triggers an increase in ribosome biosynthesis and that switching is caused by competition between ribosomes and CsrA/RsmA proteins for the mRNA transcript of a feed-forward regulator of colanic acid biosynthesis. We additionally show that in the ancestral bacterium the switch is part of a programme that determines stochastic entry into the semi-quiescent capsulated state, ensures that such cells are provisioned with excess ribosomes, and enables provisioned cells to exit rapidly from stationary phase under permissive conditions.

Investigations of Intercellular Mitochondrial Transfer in Neural Cells by Applied Single Molecule Genotyping

2021 ◽  
Author(s):  
◽  
Matthew Rowe
Keyword(s):  
Cell Line ◽  
Single Molecule ◽  
Cellular Response ◽  
Rolling Circle Amplification ◽  
Metabolic Phenotype ◽  
Neural Cells ◽  
Mitochondrial Transfer ◽  
Mitochondrial Ribosome

<p>Over the past decade and a half, evidence for transfer of whole mitochondria between mammalian cells has emerged in the literature. The notion that mitochondria are restricted to the cell of origin has been overturned by this curious phenomenon, yet the physiological relevance of these transfer events remains unclear.   This thesis investigates intercellular mitochondrial transfer in co-cultures of neural cells in vitro, to understand whether neural cells placed under stress demonstrate an enhanced rate of intercellular mitochondrial transfer. This would implicate the phenomenon as a cellular response to stress.   Reliable techniques for quantitative study of intercellular mitochondrial transfer are limited so far in this field. To address this, a novel quantitative approach was developed to detect intercellular mitochondrial transfer, based on single molecule genotyping by target-primed rolling circle amplification. This enabled imaging of individual mitochondrial DNA molecules in situ, to detect those molecules which had moved between cells. Through this strategy, intercellular mitochondrial transfer was detected in new in vitro co-culture models.   Primary murine pericytes derived from brain microvessels, were found to readily transfer mitochondria to a murine astrocyte cell line in vitro. Cisplatin, a DNA damaging agent; and chloramphenicol, a mitochondrial ribosome inhibitor, used to induce acute cellular injuries in the murine astrocyte cell line. These injuries were characterised and found to induce apoptosis, cause changes in growth characteristics, mitochondrial gene expression, and alter the metabolic phenotype of the cells. A derivative of the astrocyte cell line which completely lacks mitochondrial respiration, was found to model a chronic metabolic injury.  As pericytes are prevalent throughout the brain, the pericyte/astrocyte co-culture model was selected to evaluate how the rate of intercellular mitochondrial transfer was altered, when the astrocytes were injured prior to co-culture. Through in situ single molecule genotyping and high throughput confocal microscopy, quantitative data was produced on how the rate of intercellular mitochondrial transfer was altered by injury in these models. The rate of intercellular mitochondrial transfer remained unaltered by chloramphenicol, however both cisplatin and the chronic metabolic injury model demonstrated reduced numbers of pericyte mitochondrial DNAs transferred into the injured astrocytes.   These studies demonstrate successful application of a novel approach to study intercellular mitochondrial transfer and enable quantitative studies of this phenomenon.</p>

scholarly journals Characterization of a head and neck cancer-derived cell line panel confirms the distinct TP53-proficient copy number-silent subclass

Oral Oncology ◽  
2019 ◽  
Vol 98 ◽  
pp. 53-61 ◽  
Author(s):  
Anne M. van Harten ◽  
Jos B. Poell ◽  
Marijke Buijze ◽  
Arjen Brink ◽  
Susanne I. Wells ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Cell Line ◽  
Neck Cancer ◽  
Copy Number ◽  
Cell Line Panel
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