title: 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)-delta 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 PKCdelta and caspase-3. Constitutive SUMOylation facilitated 1% O(2)- or DFO-induced nuclear factor kappaB 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, PKCdelta, caspase-3, and nuclear factor kappaB signaling pathways modulate salivary adaptive responses to stress in cells exposed to either 1% O(2) or DFO.
authors.affiliation: Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles 90033-1049, USA.
authors.forename: Ha-Van
authors.initials: HV
authors.lastname: Nguyen
authors.forename: Jo-Lin
authors.initials: JL
authors.lastname: Chen
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhong
authors.forename: Kwang-Jin
authors.initials: KJ
authors.lastname: Kim
authors.forename: Edward D
authors.initials: ED
authors.lastname: Crandall
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D003676:Deferoxamine; D004847:Epithelial Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D025842:SUMO-1 Protein / Q000378:metabolism* / Q000502:physiology; D012469:Salivary Glands / Q000166:cytology*; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
chemical_list: D000199:Actins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D025842:SUMO-1 Protein; C569042:TJP1 protein, human; C569044:Tjp1 protein, rat; D025521:Tumor Suppressor Proteins; D062826:Zonula Occludens-1 Protein; C497260:Prkcd protein, rat; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051745:Protein Kinase C-delta; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003676:Deferoxamine