title: Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival.
abstract: Epidermal growth factor receptor (EGFR) is a cell surface receptor that has an essential role in cell proliferation and survival, and overexpression of EGFR is a common feature of human cancers. In Non-small-cell lung cancer (NSCLC), activating mutations of EGFR have also been described. We recently showed that mutant EGFR-L858R inhibits the expression of the p14ARF tumor-suppressor protein to promote cell survival. In this study, we defined the molecular bases by which EGFR controls Arf expression. Using various lung tumor models, we showed that EGF stimulation inhibits Arf transcription by a mechanism involving the nuclear transport and recruitment of EGFR to the Arf promoter. We unraveled the vesicular trafficking protein Vps34 as a mediator of EGFR nuclear trafficking and showed that its neutralization prevents the accumulation of EGFR to the Arf promoter in response to ligand activation. Finally, in lung tumor cells that carry mutant EGFR-L858R, we demonstrated that inhibition of Vps34 using small interfering RNA restrains nuclear EGFR location and restores Arf expression leading to apoptosis. These findings identify the Arf tumor suppressor as a new transcriptional target of nuclear EGFR and highlight Vps34 as an important regulator of the nuclear EGFR/Arf survival pathway. As a whole, they provide a mechanistic explanation to the inverse correlation between nuclear expression of EGFR and overall survival in NSCLC patients.
authors.affiliation: Equipe Bases Moléculaires de la Progression des Cancers du Poumon, Centre de Recherche INSERM U823, Grenoble, France.|Université Joseph Fourier, Institut Albert Bonniot, Grenoble, France.
authors.forename: D
authors.initials: D
authors.lastname: Dayde
authors.affiliation: Equipe Bases Moléculaires de la Progression des Cancers du Poumon, Centre de Recherche INSERM U823, Grenoble, France.|Université Joseph Fourier, Institut Albert Bonniot, Grenoble, France.
authors.forename: M
authors.initials: M
authors.lastname: Guerard
authors.affiliation: Equipe Bases Moléculaires de la Progression des Cancers du Poumon, Centre de Recherche INSERM U823, Grenoble, France.|Université Joseph Fourier, Institut Albert Bonniot, Grenoble, France.
authors.forename: P
authors.initials: P
authors.lastname: Perron
authors.affiliation: Equipe Bases Moléculaires de la Progression des Cancers du Poumon, Centre de Recherche INSERM U823, Grenoble, France.|Université Joseph Fourier, Institut Albert Bonniot, Grenoble, France.
authors.forename: A-S
authors.initials: AS
authors.lastname: Hatat
authors.affiliation: Equipe Bases Moléculaires de la Progression des Cancers du Poumon, Centre de Recherche INSERM U823, Grenoble, France.|Université Joseph Fourier, Institut Albert Bonniot, Grenoble, France.
authors.forename: C
authors.initials: C
authors.lastname: Barrial
authors.affiliation: Equipe Bases Moléculaires de la Progression des Cancers du Poumon, Centre de Recherche INSERM U823, Grenoble, France.|Université Joseph Fourier, Institut Albert Bonniot, Grenoble, France.
authors.forename: B
authors.initials: B
authors.lastname: Eymin
authors.affiliation: Equipe Bases Moléculaires de la Progression des Cancers du Poumon, Centre de Recherche INSERM U823, Grenoble, France.|Université Joseph Fourier, Institut Albert Bonniot, Grenoble, France.
authors.forename: S
authors.initials: S
authors.lastname: Gazzeri
mesh_terms: D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival; D058546:Class III Phosphatidylinositol 3-Kinases / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF; D058546:Class III Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt