Mammalian sterile 20-like kinase 3 (MST3) mediates oxidative-stress-induced cell death by modulating JNK activation

• Published in: Bioscience reports Vol. 29; no. 6; pp. 405 - 415
• Main Authors: Chen, Ce-Belle, Ng, Jowin K W, Choo, Poh-Heok, Wu, Wei, Porter, Alan G
• Format: Journal Article
• Language: English
• Published: England 01.12.2009
• Subjects: Apoptosis - physiology; Cell Line, Tumor; Enzyme Activation; Heme Oxygenase-1 - metabolism; Humans; Hydrogen Peroxide - pharmacology; JNK Mitogen-Activated Protein Kinases - metabolism; Oxidative Stress - drug effects; Oxidative Stress - physiology; Phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism
• ISSN: 0144-8463; 1573-4935
• DOI: 10.1042/BSR20090096

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.