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Cancer Prev Res (Phila). 2014 Dec;7(12):1270-81. doi: 10.1158/1940-6207.CAPR-14-0233. Epub 2014 Oct 3.

Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the cheliensisin a inhibition of cell transformation.

Author information

  • 1Nelson 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.
  • 2Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
  • 3State Key Laboratory of Phytochemistry and Plant Resources in West China and Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
  • 4Zhejiang 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.
  • 5State 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.
  • 6Nelson 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.

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.

PMID:
25281487
PMCID:
PMC4256147
DOI:
10.1158/1940-6207.CAPR-14-0233
[PubMed - indexed for MEDLINE]
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