A test of highly optimized tolerance reveals fragile cell-cycle mechanisms are molecular targets in clinical cancer trials.

Robustness, a long-recognized property of living systems, allows function in the face of uncertainty while fragility, i.e., extreme sensitivity, can potentially lead to catastrophic failure following seemingly innocuous perturbations. Carlson and Doyle hypothesized that highly-evolved networks, e.g....

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Autores principales:	Satyaprakash Nayak, Saniya Salim, Deyan Luan, Michael Zai, Jeffrey D Varner
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6015800c8a134424b3c02cacc2536f44
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spelling	oai:doaj.org-article:6015800c8a134424b3c02cacc2536f442021-11-25T06:12:43ZA test of highly optimized tolerance reveals fragile cell-cycle mechanisms are molecular targets in clinical cancer trials.1932-620310.1371/journal.pone.0002016https://doaj.org/article/6015800c8a134424b3c02cacc2536f442008-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18431497/?tool=EBIhttps://doaj.org/toc/1932-6203Robustness, a long-recognized property of living systems, allows function in the face of uncertainty while fragility, i.e., extreme sensitivity, can potentially lead to catastrophic failure following seemingly innocuous perturbations. Carlson and Doyle hypothesized that highly-evolved networks, e.g., those involved in cell-cycle regulation, can be resistant to some perturbations while highly sensitive to others. The "robust yet fragile" duality of networks has been termed Highly Optimized Tolerance (HOT) and has been the basis of new lines of inquiry in computational and experimental biology. In this study, we tested the working hypothesis that cell-cycle control architectures obey the HOT paradigm. Three cell-cycle models were analyzed using monte-carlo sensitivity analysis. Overall state sensitivity coefficients, which quantify the robustness or fragility of a given mechanism, were calculated using a monte-carlo strategy with three different numerical techniques along with multiple parameter perturbation strategies to control for possible numerical and sampling artifacts. Approximately 65% of the mechanisms in the G1/S restriction point were responsible for 95% of the sensitivity, conversely, the G2-DNA damage checkpoint showed a much stronger dependence on a few mechanisms; approximately 32% or 13 of 40 mechanisms accounted for 95% of the sensitivity. Our analysis predicted that CDC25 and cyclin E mechanisms were strongly implicated in G1/S malfunctions, while fragility in the G2/M checkpoint was predicted to be associated with the regulation of the cyclin B-CDK1 complex. Analysis of a third model containing both G1/S and G2/M checkpoint logic, predicted in addition to mechanisms already mentioned, that translation and programmed proteolysis were also key fragile subsystems. Comparison of the predicted fragile mechanisms with literature and current preclinical and clinical trials suggested a strong correlation between efficacy and fragility. Thus, when taken together, these results support the working hypothesis that cell-cycle control architectures are HOT networks and establish the mathematical estimation and subsequent therapeutic exploitation of fragile mechanisms as a novel strategy for anti-cancer lead generation.Satyaprakash NayakSaniya SalimDeyan LuanMichael ZaiJeffrey D VarnerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 4, p e2016 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Satyaprakash Nayak Saniya Salim Deyan Luan Michael Zai Jeffrey D Varner A test of highly optimized tolerance reveals fragile cell-cycle mechanisms are molecular targets in clinical cancer trials.
description	Robustness, a long-recognized property of living systems, allows function in the face of uncertainty while fragility, i.e., extreme sensitivity, can potentially lead to catastrophic failure following seemingly innocuous perturbations. Carlson and Doyle hypothesized that highly-evolved networks, e.g., those involved in cell-cycle regulation, can be resistant to some perturbations while highly sensitive to others. The "robust yet fragile" duality of networks has been termed Highly Optimized Tolerance (HOT) and has been the basis of new lines of inquiry in computational and experimental biology. In this study, we tested the working hypothesis that cell-cycle control architectures obey the HOT paradigm. Three cell-cycle models were analyzed using monte-carlo sensitivity analysis. Overall state sensitivity coefficients, which quantify the robustness or fragility of a given mechanism, were calculated using a monte-carlo strategy with three different numerical techniques along with multiple parameter perturbation strategies to control for possible numerical and sampling artifacts. Approximately 65% of the mechanisms in the G1/S restriction point were responsible for 95% of the sensitivity, conversely, the G2-DNA damage checkpoint showed a much stronger dependence on a few mechanisms; approximately 32% or 13 of 40 mechanisms accounted for 95% of the sensitivity. Our analysis predicted that CDC25 and cyclin E mechanisms were strongly implicated in G1/S malfunctions, while fragility in the G2/M checkpoint was predicted to be associated with the regulation of the cyclin B-CDK1 complex. Analysis of a third model containing both G1/S and G2/M checkpoint logic, predicted in addition to mechanisms already mentioned, that translation and programmed proteolysis were also key fragile subsystems. Comparison of the predicted fragile mechanisms with literature and current preclinical and clinical trials suggested a strong correlation between efficacy and fragility. Thus, when taken together, these results support the working hypothesis that cell-cycle control architectures are HOT networks and establish the mathematical estimation and subsequent therapeutic exploitation of fragile mechanisms as a novel strategy for anti-cancer lead generation.
format	article
author	Satyaprakash Nayak Saniya Salim Deyan Luan Michael Zai Jeffrey D Varner
author_facet	Satyaprakash Nayak Saniya Salim Deyan Luan Michael Zai Jeffrey D Varner
author_sort	Satyaprakash Nayak
title	A test of highly optimized tolerance reveals fragile cell-cycle mechanisms are molecular targets in clinical cancer trials.
title_short	A test of highly optimized tolerance reveals fragile cell-cycle mechanisms are molecular targets in clinical cancer trials.
title_full	A test of highly optimized tolerance reveals fragile cell-cycle mechanisms are molecular targets in clinical cancer trials.
title_fullStr	A test of highly optimized tolerance reveals fragile cell-cycle mechanisms are molecular targets in clinical cancer trials.
title_full_unstemmed	A test of highly optimized tolerance reveals fragile cell-cycle mechanisms are molecular targets in clinical cancer trials.
title_sort	test of highly optimized tolerance reveals fragile cell-cycle mechanisms are molecular targets in clinical cancer trials.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/6015800c8a134424b3c02cacc2536f44
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A test of highly optimized tolerance reveals fragile cell-cycle mechanisms are molecular targets in clinical cancer trials.

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