Recent progress and open challenges in modeling p53 dynamics in single cells

Batchelor, Eric; Loewer, Alexander

doi:10.1016/j.coisb.2017.04.007

Cited by 21 publications

(27 citation statements)

References 49 publications

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“…Aspects of these ATR/ATM-mediated molecular responses to DNA damage induced by agents such as cisplatin and UVC are strongly dose-and time-dependent [41][42][43][44][45]. We will illustrate this here by reference to an early study by Latonen et al [41].…”

Section: Roles Of P53 In Cellular Responses To Genotoxic/oxidative Stmentioning

confidence: 93%

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

Murray

Mirzayans

2020

IJMS

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Chemotherapy is intended to induce cancer cell death through apoptosis and other avenues. Unfortunately, as discussed in this article, moderate doses of genotoxic drugs such as cisplatin typical of those achieved in the clinic often invoke a cytostatic/dormancy rather than cytotoxic/apoptosis response in solid tumour-derived cell lines. This is commonly manifested by an extended apoptotic threshold, with extensive apoptosis only being seen after very high/supralethal doses of such agents. The dormancy response can be associated with senescence-like features, polyploidy and/or multinucleation, depending in part on the p53 status of the cells. In most solid tumour-derived cells, dormancy represents a long-term survival mechanism, ultimately contributing to disease recurrence. This review highlights the nonlinearity of key aspects of the molecular and cellular responses to bulky DNA lesions in human cells treated with chemotherapeutic drugs (e.g., cisplatin) or ultraviolet light-C (a widely used tool for unraveling details of the DNA damage-response) as a function of the level of genotoxic stress. Such data highlight the growing realization that targeting dormant cancer cells, which frequently emerge following conventional anticancer treatments, may represent a novel strategy to prevent or, at least, significantly suppress cancer recurrence.

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Section: Roles Of P53 In Cellular Responses To Genotoxic/oxidative Stmentioning

confidence: 93%

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

Murray

Mirzayans

2020

IJMS

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“…Thus, sustained or damped oscillations could simply be a byproduct of the negative feedback loops. What supports partly such a view is that a large fraction of γ -irradiated cells (≈ 40%) do not show oscillations [52] and that there is a considerable heterogeneity of p53 dynamics even in genetically identical cells [64]. p53 in nonoscillatory cells may still be regulated by the same feedback loops as in oscillatory cells with the same regulatory outcome (cell death or cell survival).…”

Section: Why Oscillations?mentioning

confidence: 99%

Frequency switching between oscillatory homeostats and the regulation of p53

Ruoff

Nishiyama

2020

Preprint

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1Homeostasis is an essential concept to understand the stability of organisms and their 2 adaptive behaviors when coping with external and internal assaults. Many hormones 3 that take part in homeostatic control come in antagonistic pairs, such as glucagon and 4 insulin reflecting the inflow and outflow compensatory mechanisms to control a certain 5 internal variable, such as blood sugar levels. By including negative feedback loops 6 homeostatic controllers can exhibit oscillations with characteristic frequencies. In this 7 paper we demonstrate the associated frequency changes in homeostatic systems when 8 individual controllers in a set of interlocked feedback loops gain control in response to 9 environmental changes. Taking p53 as an example, we show how the Per2, ATM and 10 Mdm2 feedback loops -interlocked with p53-gain individual control in dependence to 11 DNA damage and how each of these controllers provide certain functionalities in their 12 regulation of p53. In unstressed cells, the circadian regulator Per2 ensures a basic p53 13 level to allow its rapid up-regulation in case of DNA damage. When DNA damage 14 occurs the ATM controller increases the level of p53 and defends it towards uncontrolled 15 degradation, which despite DNA damage, would drive p53 to lower values and p53 16dysfunction. Mdm2 on its side keeps p53 at a maximum level to avoid premature 17 apoptosis. However, with on-going DNA damage the Mdm2 set-point is increased by 18 HSP90 and other p53 stabilizers leading finally to apoptosis. An essential aspect in p53 19 regulation at occurring cell stress is the coordinated inhibition of ubiquitin-independent 20 and ubiquitin-dependent degradation reactions and the increasing stabilizing 21 mechanisms of p53. Whether oscillations serve a function or are merely a by-product of 22 the controllers are discussed in view of the finding that homeostatic control of p53, as 23 indicated above, does in principle not require oscillatory homeostats. 24 30 control [8], alongside with integral feedback [9][10][11], and systems biology methods [12, 13]. 31 It became clear that certain reaction kinetic conditions are necessary for the occurrence 32December 24, 2019 1/17 of integral control leading to the robustness of the feedback controller. These conditions 33 include zero-order kinetics [9, 10,[14][15][16][17][18][19], autocatalysis [20][21][22], and second-order 34 (bimolecular/antithetic) reaction [23, 24], which were implemented into various controller 35 motifs, synthetic gene networks, and other negative feedback structures [18,[25][26][27]. 36A particular interesting aspect is that, under certain conditions, the homeostatic 37 controllers may become oscillatory and preserve, if integral control is present, their 38 homeostatic property by keeping the average value of the controlled variable at its 39 set-point [28]. While the occurrence of oscillations is generally avoided in control 40 engineering, natural systems show generally oscillatory behaviors, as found in circadian 41 or ultradian rhythms ...

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“…To this end, advances in single-cell assays have focused attention on the fact that intracellular biochemical fluctuations can have profound effects on phenotype (survival versus death) (reviewed in [ 7 , 9 , 10 ]). These fluctuations cause genetically identical cells (e.g., different subsets of cells within a culture of a given human cell line) to differ significantly in their responsiveness to cytotoxic stimuli even in a uniform environment [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Below we will briefly discuss the multiple (and opposing) properties of caspase-3 and reversibility of the apoptotic cascade.…”

Section: Surviving Stress-induced Apoptotic Signalingmentioning

confidence: 99%

Viability Assessment Following Anticancer Treatment Requires Single-Cell Visualization

Mirzayans

Andrais

Murray

2018

Cancers

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A subset of cells within solid tumors become highly enlarged and enter a state of dormancy (sustained proliferation arrest) in response to anticancer treatment. Although dormant cancer cells might be scored as “dead” in conventional preclinical assays, they remain viable, secrete growth-promoting factors, and can give rise to progeny with stem cell-like properties. Furthermore, cancer cells exhibiting features of apoptosis (e.g., caspase-3 activation) following genotoxic stress can undergo a reversal process called anastasis and survive. Consistent with these observations, single-cell analysis of adherent cultures (solid tumor-derived cell lines with differing p53 status) has demonstrated that virtually all cells—irrespective of their size and morphology—that remain adherent to the culture dish for a long time (weeks) after treatment with anticancer agents exhibit the ability to metabolize 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- tetrazolium bromide (MTT). The purpose of this commentary is to briefly review these findings and discuss the significance of single-cell (versus population averaged) observation methods for assessment of cancer cell viability and metabolic activity.

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Recent progress and open challenges in modeling p53 dynamics in single cells

Cited by 21 publications

References 49 publications

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

Frequency switching between oscillatory homeostats and the regulation of p53

Viability Assessment Following Anticancer Treatment Requires Single-Cell Visualization

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