Mammalian sterile 20-like kinase 3 (MST3) mediates oxidative-stress-induced cell death by modulating JNK activation.
MST3 (mammalian sterile 20-like kinase 3) is a sterile 20 kinase reported to have a role in Fas-ligation- and staurosporine-induced cell death by unknown mechanism(s). We found that MST3-deficient cells are resistant to H2O2, which was reversed by reconstituting recombinant MST3. H2O2-induced JNK (c-Jun N-terminal kinase) activation was greatly enhanced in shMST3 cells (a cell line treated with short hairpin RNA against MST3). Suppression of JNK activity by the inhibitor SP600125 or by dominant-negative JNK2 re-sensitized cells to H2O2. Furthermore, c-Jun Ser-63 phosphorylation was augmented in shMST3 cells, whereas JunAA (dominant-negative c-Jun) reduced H2O2 resistance, implicating an AP-1 (activator protein 1) pathway in H2O2-induced survival signalling. Total cytoprotective HO-1 (haem oxygenase 1) expression, which was attenuated by JunAA, was induced up to 5-fold higher in shMST3 cells compared with controls. Zinc protoporphyrin IX, a potent inhibitor of HO reversed the H2O2-resistance of shMST3 cells. Our results reveal that H2O2-induced MST3-mediated cell death involves suppressing both a JNK survival pathway and up-regulation of HO-1.
Chen
Ce-Belle
CB
Division of Cancer and Developmental Cell Biology, Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore. ce-belle.chen@green.oxon.org
Ng
Jowin K W
JK
Choo
Poh-Heok
PH
Wu
Wei
W
Porter
Alan G
AG
D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
D051547:Heme Oxygenase-1; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; C430908:STK26 protein, human; D000099317:Hippo Kinases