Bistability in Apoptosis: Roles of Bax, Bcl-2, and Mitochondrial Permeability Transition Pores

Bagci, Elife Zerrin; Vodovotz, Yoram; Billiar, Timothy R.; Ermentrout, Bard; Bahar, İvet

doi:10.1529/biophysj.105.068122

Cited by 286 publications

(285 citation statements)

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“…Experimental data and mathematical models have suggested that a transition exists from cell survival to cell death, which is controlled by threshold values. This cellular susceptibility value is determined by the relative concentrations of pro-and antiapoptotic factors, as for example, the ratio of Bcl-2 to Bax expression (Danial and Korsmeyer, 2004;Bagci et al, 2006), or the haploinsufficiency in some factors (Eischen et al, 2004;Gotz et al, 2004), or the release of subthreshold levels of cytochrome c from the mitochondria that mediate a partial caspase activation insufficient for a full apoptotic response (Cosulich et al, 1999). Our data indicate that WNK3 participates in the modulation of such apoptotic threshold values.…”

Section: Discussionmentioning

confidence: 88%

Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway

et al. 2006

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The subfamily of WNK (with no K ¼ lysine) protein kinases has four human members and germline mutations in the WNK1 and WNK4 genes were recently found to cause pseudohypoaldosteronism type II, a familial hypertension disease. Here, we describe cloning and functional analysis of a further WNK member, human WNK3. Endogenous WNK3 protein is an active protein kinase when immunoprecipitated from cells and its overexpression increases the survival of HeLa cells by delaying the onset of apoptosis. Suppression of endogenous WNK3 protein by RNA interference accelerates the apoptotic response and promotes the activation of caspase-3. The mechanism of WNK3 action involves interaction with procaspase-3 and heat-shock protein 70. These results demonstrate a role for WNK3 in promoting cell survival and suggest a mechanism at the level of procaspase-3 activation.

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Section: Discussionmentioning

confidence: 88%

Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway

et al. 2006

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“…Explaining stability under a range of variation in parameter values again requires mathematical modeling. The Eissing et al (2004) study discussed does such an analysis (for more details see Eissing et al, 2005), as do other systems biological studies of bistability in the context of apoptosis (Bagci et al, 2006;Cui et al, 2008;Ho & Harrington, 2010). The bistability modeling by Legewie et al (2006) includes both the extrinsic (death receptor initiated) and intrinsic (mitochondrion initiated) apoptosis pathway.…”

Section: Bistability: Apoptosismentioning

confidence: 99%

Systems biology and the integration of mechanistic explanation and mathematical explanation

Brigandt

2013

Studies in History and Philosophy of Science Part C: Studies in

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The paper discusses how systems biology is working toward complex accounts that integrate explanation in terms of mechanisms and explanation by mathematical models-which some philosophers have viewed as rival models of explanation. Systems biology is an integrative approach, and it strongly relies on mathematical modeling. Philosophical accounts of mechanisms capture integrative in the sense of multilevel and multifield explanations, yet accounts of mechanistic explanation (as the analysis of a whole in terms of its structural parts and their qualitative interactions) have failed to address how a mathematical model could contribute to such explanations. I discuss how mathematical equations can be explanatorily relevant. Several cases from systems biology are discussed to illustrate the interplay between mechanistic research and mathematical modeling, and I point to questions about qualitative phenomena (rather than the explanation of quantitative details), where quantitative models are still indispensable to the explanation. Systems biology shows that a broader philosophical conception of mechanisms is needed, which takes into account functional-dynamical aspects, interaction in complex networks with feedback loops, system-wide functional properties such as distributed functionality and robustness, and a mechanism's ability to respond to perturbations (beyond its actual operation). I offer general conclusions for philosophical accounts of explanation.

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“…Over-expression of p53AIP1 then induces the release of cytochrome c (CytoC) from mitochondrial caused by dissipation of mitochondrial membrane potential ⌬ m (33), and apoptosis rapidly ensues after the activation of Caspase 3 (Casp3). A positive-feedback loop between CytoC and Casp3 (36) underlies the apoptotic switch in our model (37). The dynamics of this module are described by Eqs.…”

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confidence: 99%

Cell fate decision mediated by p53 pulses

Zhang

Liu

Zhang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

219

208

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The tumor suppressor p53 plays a crucial role in cellular response to various stresses. Recent experiments have shown that p53 level exhibits a series of pulses after DNA damage caused by ionizing radiation (IR). However, how the p53 pulses govern cell survival and death remains unclear. Here, we develop an integrated model with four modules for the p53 network and explore the mechanism for cell fate decision based on the dynamics of the network. By numerical simulations, the following processes are characterized. First, DNA repair proteins bind to IR-induced double-strand breaks, forming complexes, which are then detected by ataxia telangiectasia mutated (ATM). Activated ATM initiates the p53 oscillator to produce pulses. Consequently, the target genes of p53 are selectively induced to control cell fate. We propose that p53 promotes the repair of minor DNA damage but suppresses the repair of severe damage. We demonstrate that cell fate is determined by the number of p53 pulses relying on the extent of DNA damage. At low damage levels, few p53 pulses evoke cell cycle arrest by inducing p21 and promote cell survival, whereas at high damage levels, sustained p53 pulses trigger apoptosis by inducing p53AIP1. We find that p53 can effectively maintain genomic integrity by regulating the efficiency and fidelity of DNA repair. We also show that stochasticity in the generation and repair of DNA damage leads to variability in cell fate. These findings are consistent with experimental observations and advance our understanding of the dynamics and functions of the p53 network.p53 network ͉ DNA repair ͉ apoptosis ͉ variability T he tumor suppressor protein p53 is a key mediator of cellular response to various stresses (1), and it performs its function primarily as a transcription factor, controlling the expression of a number of target genes (2). In response to DNA damage, the p53 signaling network is activated to induce cell cycle arrest, DNA repair, and apoptosis (1). Previously, it was proposed that p53 responds to DNA damage in an analog mode, i.e., a low level of p53 promotes cell survival by inducing cell cycle arrest and facilitating DNA repair, whereas a high level of p53 induces apoptosis to destroy irreparably damaged cells (1). Recently, damped oscillations of p53 level have been observed upon IR at the population level in several human cell lines and transgenic mice (3-6), with the amplitude of oscillations depending on the IR dose (5). More interestingly, pulses of p53 level were revealed in individual MCF7 cells, and the mean number of pulses, rather than the amplitude, was found to be related to the IR dose (7). This was suggested as a digital mode of p53 response (7). Later, it was further found that some MCF7 cells exhibit permanent p53 pulses whereas a few cells still show a finite number of p53 pulses during long-term observations (8). Such permanent oscillations may be related to the deficiency in DNA repair and apoptosis induction in those transformed cells (9-11). Moreover, the damped oscillations obse...

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Bistability in Apoptosis: Roles of Bax, Bcl-2, and Mitochondrial Permeability Transition Pores

Cited by 286 publications

References 57 publications

Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway

Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway

Systems biology and the integration of mechanistic explanation and mathematical explanation

Cell fate decision mediated by p53 pulses

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