title: Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the cheliensisin a inhibition of cell transformation.
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.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York. Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Jingjie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York. Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Haishan
authors.initials: H
authors.lastname: Huang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York. Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Honglei
authors.initials: H
authors.lastname: Jin
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York. Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China and Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Deng
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Chuanshu.huang@nyumc.org qinshizhao@mail.kib.ac.cn jimingao@yahoo.com.
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China and Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. Chuanshu.huang@nyumc.org qinshizhao@mail.kib.ac.cn jimingao@yahoo.com.
authors.forename: Qinshi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York. Chuanshu.huang@nyumc.org qinshizhao@mail.kib.ac.cn jimingao@yahoo.com.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology*; D005434:Flow Cytometry; D047468:Immunoprecipitation; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D004852:Epoxy Compounds; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D011753:Pyrones; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C504861:cheliensisin A; D012694:Serine; D004815:Epidermal Growth Factor; C519282:PHLPP1 protein, mouse; D010749:Phosphoprotein Phosphatases