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|Title:||Peroxynitrite promotes serine-62 phosphorylation-dependent stabilization of the oncoprotein c-Myc||Authors:||Raman, D.
Chong, Stephen J. F.
|Issue Date:||2020||Publisher:||Elsevier B.V.||Citation:||Raman, D., Chong, Stephen J. F., Iskandar, K., Hirpara, J.L., Pervaiz, S. (2020). Peroxynitrite promotes serine-62 phosphorylation-dependent stabilization of the oncoprotein c-Myc. Redox Biology 34 : 101587. ScholarBank@NUS Repository. https://doi.org/10.1016/j.redox.2020.101587||Rights:||Attribution-NonCommercial-NoDerivatives 4.0 International||Abstract:||Stabilization of c-Myc oncoprotein is dependent on post-translational modifications, especially its phosphorylation at serine-62 (S62), which enhances its tumorigenic potential. Herein we report that increase in intracellular superoxide induces phospho-stabilization and activation of c-Myc in cancer cells. Importantly, sustained phospho-S62 c-Myc was necessary for promoting superoxide dependent chemoresistance as non-phosphorylatable S62A c-Myc was insensitive to the redox impact when subjected to chemotherapeutic insults. This redox-dependent sustained S62 phosphorylation occurs through nitrative inhibition of phosphatase, PP2A, brought about by peroxynitrite, a reaction product of superoxide and nitric oxide. We identified a conserved tyrosine residue (Y238) in the c-Myc targeting subunit B56? of PP2A, which is selectively amenable to nitrative inhibition, further preventing holoenzyme assembly. In summary, we have established a novel mechanism wherein the pro-oxidant microenvironment stimulates a pro-survival milieu and reinforces tumor maintenance as a functional consequence of c-Myc activation through its sustained S62 phosphorylation via inhibition of phosphatase PP2A. Significance statement: Increased peroxynitrite signaling in tumors causes sustained S62 c-Myc phosphorylation by PP2A inhibition. This is critical to promoting c-Myc stabilization and activation which promotes chemoresistance and provides significant proliferative and growth advantages to osteosarcomas. � 2020||Source Title:||Redox Biology||URI:||https://scholarbank.nus.edu.sg/handle/10635/197699||ISSN:||22132317||DOI:||10.1016/j.redox.2020.101587||Rights:||Attribution-NonCommercial-NoDerivatives 4.0 International|
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