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This galley proof is being listed electronically before publishing the final manuscript (It's not final version).

 
p38-dependent c-Jun degradation contributes to reduced PGE2 production in sodium orthovanadate-treated macrophages
Nur Aziz1 (Graduate student), Eunji Kim1 (Research worker), Yanyan Yang1,2 (Professor), Han Gyung Kim1 (Research worker), Tao Yu1,3 (Professor), Jae Youl Cho 1,* (Professor)
1Department of Integrative Biotechnology, Sungkyunkwan University,
2Institute for Translational Medicine and 3Department of Cardiac Ultrasound, Qingdao University
Abstract
Upon activation by mitogen activated protein kinases (MAPKs), c-Jun undergoes phosphorylation, which affects its DNA binding activity and stability. The underlying mechanism and the key enzymes responsible for this phenomenon remain largely unknown. In particular, the phenomenon of c-Jun degradation in the inflammatory response has not yet been reported. To verify this, we investigated LPS-stimulated murine macrophages pre-treated with sodium orthovanadate (SO) to uncover the regulatory mechanism of the MAPKs that regulate c-Jun degradation in the inflammatory response. SO suppressed the production of prostaglandin E2 (PGE2) and the expression of COX-2 in LPS-stimulated RAW264.7 cells. SO also decreased total c-Jun levels without altering the abundance of its mRNA, although phospho-levels of p38, ERK, and JNK were strongly enhanced. By using selective MAPK inhibitors and knockdown and overexpression strategies, p38 was revealed to be a major MAPK that regulates c-Jun degradation. Further analysis indicated that the phosphorylation of p38 is a determinant for c-Jun degradation that is sufficient to induce ubiquitination-dependent c-Jun degradation, recovered by MG132 treatment. Therefore, our results suggest that hyperphosphorylation of p38 by SO contributes to c-Jun degradation linked to the suppression of PGE2 secretion in inflammatory responses; finding drugs to increase p38 activity could be a novel strategy for the development of anti-inflammatory drugs.
Abstract, Accepted Manuscript(in press) [Submitted on August 18, 2021, Accepted on March 18, 2022]
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