title: The PTEN/NRF2 axis promotes human carcinogenesis.
abstract: OBJECTIVE
  A recent study conducted in mice reported that liver-specific knockout of tumor suppressor Pten augments nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcriptional activity. Here, we further investigated how phosphatase and tensin homolog deleted on chromosome 10 (PTEN) controls NRF2 and the relevance of this pathway in human carcin ogenesis.
  
  
  RESULTS
  Drug and genetic targeting to PTEN and phosphoproteomics approaches indicated that PTEN leads to glycogen synthase kinase-3 (GSK-3)-mediated phosphorylation of NRF2 at residues Ser(335) and Ser(338) and subsequent beta-transducin repeat containing protein (β-TrCP)-dependent but Kelch-like ECH-associated protein 1 (KEAP1)-independent degradation. Rescue experiments in PTEN-deficient cells and xerographs in athymic mice indicated that loss of PTEN leads to increased NRF2 signature which provides a proliferating and tumorigenic advantage. Tissue microarrays from endometrioid carcinomas showed that 80% of PTEN-negative tumors expressed high levels of NRF2 or its target heme oxygenase-1 (HO-1).
  
  
  METHODS
  These results uncover a new mechanism of oncogenic activation of NRF2 by loss of its negative regulation by PTEN/GSK-3/β-TrCP that may be relevant to a large number of tumors, including endometrioid carcinomas.
  
  
  CONCLUSIONS
  Increased activity of NRF2 due to loss of PTEN is instrumental in human carcinogenesis and represents a novel therapeutic target.
authors.affiliation: 1 Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid , and Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Madrid, Spain .
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rojo
authors.forename: Patricia
authors.initials: P
authors.lastname: Rada
authors.forename: Marta
authors.initials: M
authors.lastname: Mendiola
authors.forename: Ana
authors.initials: A
authors.lastname: Ortega-Molina
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wojdyla
authors.forename: Adelina
authors.initials: A
authors.lastname: Rogowska-Wrzesinska
authors.forename: David
authors.initials: D
authors.lastname: Hardisson
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human