Abstract
BackgroundOxidative stress is a key feature in the pathogenesis of several neurological disorders. Following oxidative stress stimuli a wide range of pathways are activated and contribute to cellular death. The mechanism that couples c-Jun N-terminal kinase (JNK) signaling, a key pathway in stress conditions, to the small ubiquitin-related modifier (SUMO), an emerging protein in the field, is largely unknown.Methodology/Principal FindingsWith this study we investigated if SUMOylation participates in the regulation of JNK activation as well as cellular death in a model of H2O2 induced-oxidative stress. Our data show that H2O2 modulates JNK activation and induces cellular death in neuroblastoma SH-SY5Y cells. Inhibition of JNK's action with the D-JNKI1 peptide rescued cells from death. Following H2O2, SUMO-1 over-expression increased phosphorylation of JNK and exacerbated cell death, although only in conditions of mild oxidative stress. Furthermore inhibition of SUMOylation, following transfection with SENP1, interfered with JNK activation and rescued cells from H2O2 induced death. Importantly, in our model, direct interaction between these proteins can occur.Conclusions/SignificanceTaken together our results show that SUMOylation may significantly contribute to modulation of JNK activation and contribute to cell death in oxidative stress conditions.
Highlights
H2O2-induced activation of Jun Nterminal kinase (JNK) in SH-SY5Y cells In the first series of studies we examined the effect of increasing doses of H2O2 (10, 50, 75 and 100 mM) in cell death and JNK activation in undifferentiated human SH-SY5Y neuroblastoma cells
Increase in JNK phosphorylation induced by H2O2 was concentration-dependent. 50 mM H2O2 led to a 1.2860.18 fold of increase of the P-JNK/JNK ratio while a higher dose of 75 mM led to a 1.8960.21 fold of increase in comparison to control non-stimulated cells (Fig. 1E, F)
We found that H2O2-induced injury significantly increased JNK activation in SH-SY5Y
Summary
H2O2 induced oxidative stress leads to activation of c-Jun N-terminal kinase (JNK), a kinase that is strongly associated with many different stress stimuli and cell death [12,13,14,15] as well as of the SUMOylation pathway, recently associated with ischemic events and cytoprotection [16,17,18,19]. SUMO conjugates proteins through an enzymatic cascade similar to ubiquitination. The process involves a single SUMO-activating enzyme E1 (Uba2-Aos1), a SUMO-conjugating enzyme E2 (Ubc). Following oxidative stress stimuli a wide range of pathways are activated and contribute to cellular death. The mechanism that couples c-Jun Nterminal kinase (JNK) signaling, a key pathway in stress conditions, to the small ubiquitin-related modifier (SUMO), an emerging protein in the field, is largely unknown
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