title: EEF1A2 inactivates p53 by way of PI3K/AKT/mTOR-dependent stabilization of MDM4 in hepatocellular carcinoma.
abstract: Mouse Double Minute homolog 4 (MDM4) gene up-regulation often occurs in human hepatocellular carcinoma (HCC), but the molecular mechanisms responsible for its induction remain poorly understood. Here we investigated the role of the phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog/mammalian target of rapamycin (PI3K/AKT/mTOR) axis in the regulation of MDM4 levels in HCC. The activity of MDM4 and the PI3K/AKT/mTOR pathway was modulated in human HCC cell lines by way of silencing and overexpression experiments. Expression of main pathway components was analyzed in an AKT mouse model and human HCCs. MDM4 inhibition resulted in growth restraint of HCC cell lines both in vitro and in vivo. Inhibition of the PI3K-AKT and/or mTOR pathways lowered MDM4 protein levels in HCC cells and reactivated p53-dependent transcription. Deubiquitination by ubiquitin-specific protease 2a and AKT-mediated phosphorylation protected MDM4 from proteasomal degradation and increased its protein stability. The eukaryotic elongation factor 1A2 (EEF1A2) was identified as an upstream inducer of PI3K supporting MDM4 stabilization. Also, we detected MDM4 protein up-regulation in an AKT mouse model and a strong correlation between the expression of EEF1A2, activated/phosphorylated AKT, and MDM4 in human HCC (each rho > 0.8, P < 0.001). Noticeably, a strong activation of this cascade was associated with shorter patient survival.
  
  
  CONCLUSIONS
  The EEF1A2/PI3K/AKT/mTOR axis promotes the protumorigenic stabilization of the MDM4 protooncogene in human HCC by way of a posttranscriptional mechanism. The activation level of the EEF1A2/PI3K/AKT/mTOR/MDM4 axis significantly influences the survival probability of HCC patients in vivo and may thus represent a promising molecular target.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Rossella
authors.initials: R
authors.lastname: Pellegrino
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.forename: Olaf
authors.initials: O
authors.lastname: Neumann
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Kolluru
authors.forename: Josephine
authors.initials: J
authors.lastname: Wesely
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.forename: Torsten
authors.initials: T
authors.lastname: Wuestefeld
authors.forename: Sara
authors.initials: S
authors.lastname: Ladu
authors.forename: Nahla
authors.initials: N
authors.lastname: Elgohary
authors.forename: Justo Lorenzo
authors.initials: JL
authors.lastname: Bermejo
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Martin
authors.initials: M
authors.lastname: Zörnig
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
mesh_terms: D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality; D018797:Cell Cycle Proteins; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality; D008297:Male; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins / Q000502:physiology*; D020648:Peptide Elongation Factor 1 / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D020648:Peptide Elongation Factor 1; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C503234:EEF1A2 protein, human; C482775:MDM4 protein, human; C495901:TP53 protein, human; C546842:MTOR protein, human