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SUMOylation Attenuates Sensitivity toward Hypoxia- or Desferroxamine-Induced Injury by Modulating Adaptive Responses in Salivary Epithelial Cells

SUMOylation Attenuates Sensitivity toward Hypoxia- or Desferroxamine-Induced Injury by Modulating Adaptive Responses in Salivary Epithelial Cells

Abstract

Hypoxic stress activates various signal transduction pathways including posttranslational modification with the ubiquitin-like SUMO protein (SUMOylation). However, the molecular mechanisms by which SUMOylation regulates hypoxic responses remain unclear. Here, we investigated the ability of rat salivary Pa-4 epithelial cells to resist cell injury elicited by 1% O 2 - or hypoxia-mimetic desferroxamine (DFO)-stimulated SUMOylation processes. By using Pa-4 cells stably transduced with lenti-SUMO-1 and a cell-permeant peptide harboring SUMO-binding motif to interfere with SUMO-dependent protein-protein interactions, we demonstrate that SUMOylation augments cell survival against DFO treatment. This appeared to be partly mediated through attenuation of Protein Kinase C (PKC)- activation and caspase-3 cleavage, hallmarks of pro-apoptotic signaling. Intriguingly, DFO-induced phosphorylation of DNA damage marker ataxia-telangiectasia-mutated protein S1981 preceded activation of PKC and caspase-3. Constitutive SUMOylation facilitated 1% O 2 - or DFO-induced nuclear factor B transactivation, possibly via activation of genotoxic signaling cascade. In addition, we observed transient preservation of transepithelial electrical resistance during the early stage of hypoxia (1% O 2 ) as well as enhanced transepithelial electrical resistance recovery after prolonged hypoxia in SUMO-1-expressing cell monolayers. In conclusion, our results unveil a previously unrecognized mechanism by which SUMOylation and activation of ataxia-telangiectasia-mutated protein, PKC , caspase-3, and nuclear factor B signaling pathways modulate salivary adaptive responses to stress in cells exposed to either 1% O 2 or DFO.
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