title: A Systems Biological View of Life-and-Death Decision with Respect to Endoplasmic Reticulum Stress-The Role of PERK Pathway.
abstract: Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER) leads to the activation of three branches (Protein kinase (RNA)-like endoplasmic reticulum kinase [PERK], Inositol requiring protein 1 [IRE-1] and Activating trascription factor 6 [ATF6], respectively) of unfolded protein response (UPR). The primary role of UPR is to try to drive back the system to the former or a new homeostatic state by self-eating dependent autophagy, while excessive level of ER stress results in apoptotic cell death. Our study focuses on the role of PERK- and IRE-1-induced arms of UPR in life-or-death decision. Here we confirm that silencing of PERK extends autophagy-dependent survival, whereas the IRE-1-controlled apoptosis inducer is downregulated during ER stress. We also claim that the proper order of surviving and self-killing mechanisms is controlled by a positive feedback loop between PERK and IRE-1 branches. This regulatory network makes possible a smooth, continuous activation of autophagy with respect to ER stress, while the induction of apoptosis is irreversible and switch-like. Using our knowledge of molecular biological techniques and systems biological tools we give a qualitative description about the dynamical behavior of PERK- and IRE-1-controlled life-or-death decision. Our model claims that the two arms of UPR accomplish an altered upregulation of autophagy and apoptosis inducers during ER stress. Since ER stress is tightly connected to aging and age-related degenerative disorders, studying the signaling pathways of UPR and their role in maintaining ER proteostasis have medical importance.
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1094 Budapest, Hungary. marton.margita@med.semmelweis-univ.hu.
authors.forename: Margita
authors.initials: M
authors.lastname: Márton
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1094 Budapest, Hungary. kurucz.anita@med.semmelweis-univ.hu.
authors.forename: Anita
authors.initials: A
authors.lastname: Kurucz
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1094 Budapest, Hungary. lizak.beata@med.semmelweis-univ.hu.
authors.forename: Beáta
authors.initials: B
authors.lastname: Lizák
authors.affiliation: Institute of Clinical Experimental Research, Semmelweis University, 1085 Budapest, Hungary. margittai.eva@med.semmelweis-univ.hu.
authors.forename: Éva
authors.initials: É
authors.lastname: Margittai
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1094 Budapest, Hungary. banhegyi@eok.sote.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Bánhegyi
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1094 Budapest, Hungary. kapuy.orsolya@med.semmelweis-univ.hu.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kapuy
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D015153:Blotting, Western; D002470:Cell Survival / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D015870:Gene Expression; D057809:HEK293 Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D049490:Systems Biology / Q000379:methods*; D056811:Unfolded Protein Response / Q000235:genetics; D019892:eIF-2 Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases
keywords: apoptosis; autophagy; dynamical behavior; endoplasmic reticulum stress