title: mTOR inhibition increases cell viability via autophagy induction during endoplasmic reticulum stress - An experimental and modeling study.
abstract: Unfolded or misfolded proteins in the endoplasmic reticulum (ER) trigger an adaptive ER stress response known as unfolded protein response (UPR). Depending on the severity of ER stress, either autophagy-controlled survival or apoptotic cell death can be induced. The molecular mechanisms by which UPR controls multiple fate decisions have started to emerge. One such molecular mechanism involves a master regulator of cell growth, mammalian target of rapamycin (mTOR), which paradoxically is shown to have pro-apoptotic role by mutually interacting with ER stress response. How the interconnections between UPR and mTOR influence the dynamics of autophagy and apoptosis activation is still unclear. Here we make an attempt to explore this problem by using experiments and mathematical modeling. The effect of perturbed mTOR activity in ER stressed cells was studied on autophagy and cell viability by using agents causing mTOR pathway inhibition (such as rapamycin or metyrapone). We observed that mTOR inhibition led to an increase in cell viability and was accompanied by an increase in autophagic activity. It was also shown that autophagy was activated under conditions of severe ER stress but that in the latter phase of stress it was inhibited at the time of apoptosis activation. Our mathematical model shows that both the activation threshold and temporal dynamics of autophagy and apoptosis inducers are sensitive to variation in mTOR activity. These results confirm that autophagy has cytoprotective role and is activated in mutually exclusive manner with respect to ER stress levels.
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Tűzoltó utca 37-47, Budapest H-1094, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kapuy
authors.affiliation: Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: P K
authors.initials: PK
authors.lastname: Vinod
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Tűzoltó utca 37-47, Budapest H-1094, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Bánhegyi
keywords: Apoptosis; Autophagy; ER, endoplasmic reticulum; Endoplasmic reticulum stress; Metyrapone; UPR, unfolded protein response; Unfolded protein response; mTOR; mTOR, mammalian target of rapamycin