title: Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN.
abstract: Although most oncogenic phenotypes of PTEN loss are attributed to AKT activation, AKT alone is not sufficient to induce all of the biological activities associated with PTEN inactivation. We searched for additional PTEN-regulated pathways through gene set enrichment analysis (GSEA) and identified genes associated with JNK activation. PTEN null cells exhibit higher JNK activity, and genetic studies demonstrate that JNK functions parallel to and independently of AKT. Furthermore, PTEN deficiency sensitizes cells to JNK inhibition and negative feedback regulation of PI3K was impaired in PTEN null cells. Akt and JNK activation are highly correlated in human prostate cancer. These findings implicate JNK in PI3K-driven cancers and demonstrate the utility of GSEA to identify functional pathways using genetically defined systems.
authors.affiliation: Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Vivanco
authors.forename: Nicolaos
authors.initials: N
authors.lastname: Palaskas
authors.forename: Chris
authors.initials: C
authors.lastname: Tran
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Finn
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Kennedy
authors.forename: Jing
authors.initials: J
authors.lastname: Jiao
authors.forename: Joshua
authors.initials: J
authors.lastname: Rose
authors.forename: Wanling
authors.initials: W
authors.lastname: Xie
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Todd
authors.initials: T
authors.lastname: Golub
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human