Peroxynitrite promotes serine-62 phosphorylation-dependent stabilization of the oncoprotein c-Myc.

Redox Biology
Deepika RamanShazib Pervaiz

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 B56α 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 signa...Continue Reading

Methods Mentioned

BETA
ubiquitination
Immunoprecipitation
transfection
gene knockdown
proximity ligation assay
PLA
co-IP
Assay

Software Mentioned

Clono
Counter
Clono counter
Seahorse XF Analyzer

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