Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.

<h4>Background</h4>The complex interplay between B-cell lymphoma 2 (Bcl-2) family proteins constitutes a crucial checkpoint in apoptosis. Its detailed molecular mechanism remains controversial. Our former modeling studies have selected the 'Direct Activation Model' as a better...

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Autores principales:	Jun Cui, Chun Chen, Haizhu Lu, Tingzhe Sun, Pingping Shen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/117c13c06f364478a72127ca88545c10
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spelling	oai:doaj.org-article:117c13c06f364478a72127ca88545c102021-11-25T06:13:36ZTwo independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.1932-620310.1371/journal.pone.0001469https://doaj.org/article/117c13c06f364478a72127ca88545c102008-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18213378/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The complex interplay between B-cell lymphoma 2 (Bcl-2) family proteins constitutes a crucial checkpoint in apoptosis. Its detailed molecular mechanism remains controversial. Our former modeling studies have selected the 'Direct Activation Model' as a better explanation for experimental observations. In this paper, we continue to extend this model by adding interactions according to updating experimental findings.<h4>Methodology/principal findings</h4>Through mathematical simulation we found bistability, a kind of switch, can arise from a positive (double negative) feedback in the Bcl-2 interaction network established by anti-apoptotic group of Bcl-2 family proteins. Moreover, Bax/Bak auto-activation as an independent positive feedback can enforce the bistability, and make it more robust to parameter variations. By ensemble stochastic modeling, we also elucidated how intrinsic noise can change ultrasensitive switches into gradual responses. Our modeling result agrees well with recent experimental data where bimodal Bax activation distributions in cell population were found.<h4>Conclusions/significance</h4>Along with the growing experimental evidences, our studies successfully elucidate the switch mechanism embedded in the Bcl-2 interaction network and provide insights into pharmacological manipulation of Bcl-2 apoptotic switch as further cancer therapies.Jun CuiChun ChenHaizhu LuTingzhe SunPingping ShenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 1, p e1469 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jun Cui Chun Chen Haizhu Lu Tingzhe Sun Pingping Shen Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.
description	<h4>Background</h4>The complex interplay between B-cell lymphoma 2 (Bcl-2) family proteins constitutes a crucial checkpoint in apoptosis. Its detailed molecular mechanism remains controversial. Our former modeling studies have selected the 'Direct Activation Model' as a better explanation for experimental observations. In this paper, we continue to extend this model by adding interactions according to updating experimental findings.<h4>Methodology/principal findings</h4>Through mathematical simulation we found bistability, a kind of switch, can arise from a positive (double negative) feedback in the Bcl-2 interaction network established by anti-apoptotic group of Bcl-2 family proteins. Moreover, Bax/Bak auto-activation as an independent positive feedback can enforce the bistability, and make it more robust to parameter variations. By ensemble stochastic modeling, we also elucidated how intrinsic noise can change ultrasensitive switches into gradual responses. Our modeling result agrees well with recent experimental data where bimodal Bax activation distributions in cell population were found.<h4>Conclusions/significance</h4>Along with the growing experimental evidences, our studies successfully elucidate the switch mechanism embedded in the Bcl-2 interaction network and provide insights into pharmacological manipulation of Bcl-2 apoptotic switch as further cancer therapies.
format	article
author	Jun Cui Chun Chen Haizhu Lu Tingzhe Sun Pingping Shen
author_facet	Jun Cui Chun Chen Haizhu Lu Tingzhe Sun Pingping Shen
author_sort	Jun Cui
title	Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.
title_short	Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.
title_full	Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.
title_fullStr	Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.
title_full_unstemmed	Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.
title_sort	two independent positive feedbacks and bistability in the bcl-2 apoptotic switch.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/117c13c06f364478a72127ca88545c10
work_keys_str_mv	AT juncui twoindependentpositivefeedbacksandbistabilityinthebcl2apoptoticswitch AT chunchen twoindependentpositivefeedbacksandbistabilityinthebcl2apoptoticswitch AT haizhulu twoindependentpositivefeedbacksandbistabilityinthebcl2apoptoticswitch AT tingzhesun twoindependentpositivefeedbacksandbistabilityinthebcl2apoptoticswitch AT pingpingshen twoindependentpositivefeedbacksandbistabilityinthebcl2apoptoticswitch
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Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.

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