title: A Comprehensive Systems Biological Study of Autophagy-Apoptosis Crosstalk during Endoplasmic Reticulum Stress.
abstract: One of the most important tasks of a living organism is to maintain its genetic integrity with respect to stress. Endoplasmic reticulum (ER) has a crucial role in sensing cellular homeostasis by controlling metabolism, proteostasis, and several signaling processes. ER stressors can induce autophagy-dependent survival; however excessive level of stress results in apoptotic cell death. Although many molecular components of these networks have already been discovered, the analysis of the dynamical features of the regulatory network of life-or-death decision is still lacking. Our goal was to incorporate both theoretical and molecular biological techniques to explore the autophagy-apoptosis crosstalk under ER stress. Using various levels of different ER stressors we confirmed that the control network always generated an evidently detectable autophagy-dependent threshold for apoptosis activation. We explored the features of this threshold by introducing both autophagy activators and inhibitors, and transient treatment with excessive level of ER stressor was also performed. Our experimental data were also supported by a stochastic approach. Our analysis suggests that even if the switch-like characteristic of apoptosis activation is hardly seen on population level the double negative feedback loop between autophagy and apoptosis inducers introduces bistability in the control network.
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Tűzoltó Utca 37-47, Budapest 1094, Hungary.
authors.forename: Marianna
authors.initials: M
authors.lastname: Holczer
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Tűzoltó Utca 37-47, Budapest 1094, Hungary.
authors.forename: Margita
authors.initials: M
authors.lastname: Márton
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Tűzoltó Utca 37-47, Budapest 1094, Hungary.
authors.forename: Anita
authors.initials: A
authors.lastname: Kurucz
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Tűzoltó Utca 37-47, Budapest 1094, Hungary.
authors.forename: Gábor
authors.identifier: 0000-0002-3315-0780
authors.initials: G
authors.lastname: Bánhegyi
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Tűzoltó Utca 37-47, Budapest 1094, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kapuy
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004229:Dithiothreitol / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008954:Models, Biological; D013269:Stochastic Processes; D013997:Time Factors; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D014415:Tunicamycin; D004229:Dithiothreitol