Margita Márton1, Gábor Bánhegyi2, Orsolya Kapuy3
1,2,3 Semmelweis University, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Budapest
One of the most important tasks of living organisms is to make an appropriate response against cellular stress events. Accumulation of misfolded proteins leads to ER stress which activates the three branches of unfolded protein response (UPR) driven by IRE1, PERK and ATF6 proteins. The main role of UPR is to avoid cell damage in respond to ER stress and to restore the homeostatic state by self-cannibalism dependent autophagy. However, excessive level of ER stress results in apoptotic cell death. PERK induces ATF4 transcription factor that has two targets, called CHOP and Gadd34. While CHOP mainly controls gene transcription involved in apoptosis, the role of Gadd34 seems to be unclear. Our hypothesis is that Gadd34 has a key role in autophagy induction upon ER stress. This immediately arises a question, namely how the two different stress response mechanisms (i.e. autophagy and apoptosis) can be regulated by the same PERK pathway.
Our goal is to give a qualitative description about the dynamical behaviour of the control system by exploring the dynamical profile of the key regulatory components.
We used both molecular biological techniques and systems biological tools.
We confirmed a strict order between autophagy and apoptosis, regulated by PERK pathway. We followed the activation of the crucial elements of PERK pathway both on protein and mRNA level during ER stress. Gadd34 activated even at tolerable level of ER stress, which correlates with autophagy induction and always precedes the appearance of CHOP. The protein level of CHOP shows a switch-like increase only when ER stress is non-tolerable.
The feedback loops between PERK targets seem to be pivotal in the life-or-death decision making process depending on the level of ER stress.
Doctoral School: Károly Rácz School of PhD Studies, Molecular Medicine
Supervisor: Orsolya Kapuy
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