Zhu, Xinzhou. The cold-inducible RNA-binding motif protein 3 (RBM3) prevents cell death through various mechanisms. 2016, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_11720
The goal of the thesis was to figure out the mechanisms of RBM3 action in cytoprotection when cells are exposed to various stressors. In an in vitro hypoxic-ischemic model, we noticed that hippocampal neural cells were protected by moderate hypothermia, accompanied with an induction of RBM3. In HEK293 cells, RBM3 enhanced cell viability and suppressed oxidative stress-induced apoptosis. In particular, we focused on endoplasmic reticulum (ER) stress because recent studies suggest that ER stress activates unfolded protein response (UPR) and eventually causes apoptosis in brain injuries and neurodegenerative diseases. In order to examine the hypothesis that RBM3 influences cell fate via regulating UPR, we challenged organotypic hippocampal slice cultures with ER stress inducers and observed exacerbated PERK-eIF2α-CHOP signaling in RBM3 knockout mice compared to wildtype mice. Furthermore, in HEK293 cells RBM3 attenuated PERK-eIF2α-CHOP signaling by inhibiting PERK phosphorylation. However, RBM3 neither interacted with PERK directly, nor altered the expression of ER stress sensor BiP. An interactome analysis of RBM3 in HEK293 cells revealed nuclear factor NF90 as a novel binding partner of RBM3 and PERK. Notably, NF90 was required for RBM3-mediated regulation of PERK activity. In addition, during our research we noticed that RBM3 downregulated a subset of pro-apoptotic miRNAs while upregulated a group of anti-apoptotic miRNAs, which may also contribute to its anti-apoptotic activity. In summary, this study confirmed the cytoprotective role of RBM3, and revealed underlying molecular mechanisms including the prevention of oxidative stress-induced apoptosis, the inhibition of PERK-eIF2α-CHOP signaling and the modulation of apoptosis-related miRNAs.
|Advisors:||Wellmann, Sven and Kapfhammer, Josef and Spang, Anne|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Division of Anatomy > Developmental Neurobiology and Regeneration (Kapfhammer)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||1 Online-Ressource (106 Seiten)|
|Last Modified:||04 Jul 2016 09:43|
|Deposited On:||04 Jul 2016 09:34|
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