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Essential role of mitochondrial Stat3 in p38(MAPK) mediated apoptosis under oxidative stress
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, 15388Article in journal (Refereed) Published
Abstract [en]

Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3(Y705) contributes to its nucleic translocation, while phospho-Stat3(S727) leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well-characterized signaling pathways interplaying with Stat3(Y705), little is known about Stat3(S727). In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to H2O2 or hypoxia using siRNA and CRISPR/Cas9 genome-editing. We found dysregulation of mitochondrial activity, which was associated with excessive ROS formation and reduced mitochondrial membrane potential, and observed a synergistic effect for oxidative stress-mediated apoptosis in Stat3-KD cells or cells carrying Stat3(Y705F), but not Stat3(S727D), suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38(MAPK) was involved and adding antioxidants, p38(MAPK) inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38(MAPK)-mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017. Vol. 7, no 1, 15388
National Category
Natural Sciences Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-334697DOI: 10.1038/s41598-017-15342-4ISI: 000415022900024PubMedID: 29133922OAI: oai:DiVA.org:uu-334697DiVA: diva2:1160340
Available from: 2017-11-27 Created: 2017-11-27 Last updated: 2017-11-27Bibliographically approved

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Peuckert, Christiane

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