Title: Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the cheliensisin a inhibition of cell transformation.
Authors: Zhu, Junlan; Zhang, Jingjie; Huang, Haishan; Li, Jingxia; Yu, Yonghui; Jin, Honglei; Li, Yang; Deng, Xu; Gao, Jimin; Zhao, Qinshi; Huang, Chuanshu
Published In Cancer Prev Res (Phila), (2014 Dec)
Abstract: Cheliensisin A (Chel A), as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been demonstrated to have an inhibition of EGF-induced Cl41 cell transformation via stabilizing p53 protein in a Chk1-dependent manner, suggesting its chemopreventive activity in our previous studies. However, its underlying molecular mechanisms have not been fully characterized yet. In the current study, we found that Chel A treatment could increase c-Jun protein phosphorylation and activation, whereas the inhibition of c-Jun phosphorylation, by ectopic expression of a dominant-negative mutant of c-Jun, TAM67, reversed the Chel A inhibition of EGF-induced cell transformation and impaired Chel A induction of p53 protein and apoptosis. Moreover, our results indicated that Chel A treatment led to a PHLPP downregulation by promoting PHLPP protein degradation. We also found that PHLPP could interact with and bind to c-Jun protein, whereas ectopic PHLPP expression blocked c-Jun activation, p53 protein and apoptotic induction by Chel A, and further reversed the Chel A inhibition of EGF-induced cell transformation. With the findings, we have demonstrated that Chel A treatment promotes a PHLPP protein degradation, which can bind to c-Jun and mediates c-Jun phosphorylation, and further leading to p53 protein induction, apoptotic responses, subsequently resulting in cell transformation inhibition and chemopreventive activity of Chel A.
PubMed ID: 25281487
MeSH Terms: Animals; Blotting, Western; Cell Proliferation; Cell Transformation, Neoplastic/drug effects*; Cell Transformation, Neoplastic/pathology; Cells, Cultured; Epidermal Growth Factor/pharmacology; Epidermis/cytology; Epidermis/drug effects*; Epidermis/metabolism; Epoxy Compounds/pharmacology*; Flow Cytometry; Immunoprecipitation; Mice; Nuclear Proteins/metabolism*; Phosphoprotein Phosphatases/metabolism*; Phosphorylation/drug effects; Proteolysis/drug effects*; Proto-Oncogene Proteins c-jun/metabolism*; Pyrones/pharmacology*; RNA, Messenger/genetics; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Serine/metabolism; Signal Transduction/drug effects*; Tumor Suppressor Protein p53/metabolism