title: A new tumor suppressor role for the Notch pathway in bladder cancer.
abstract: The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.
authors.affiliation: Biomedical Research Foundation Academy of Athens, Athens, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Rampias
authors.affiliation: Biomedical Research Foundation Academy of Athens, Athens, Greece.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Vgenopoulou
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, Greece.
authors.forename: Margaritis
authors.initials: M
authors.lastname: Avgeris
authors.affiliation: Biomedical Research Foundation Academy of Athens, Athens, Greece.
authors.forename: Alexander
authors.initials: A
authors.lastname: Polyzos
authors.affiliation: First Department of Urology, 'Laiko' General Hospital, Medical School, University of Athens, Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Stravodimos
authors.affiliation: Molecular Pathology Unit, Department of Pathology, Metaxa Cancer Hospital, Piraeus, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Valavanis
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Scorilas
authors.affiliation: Biomedical Research Foundation Academy of Athens, Athens, Greece.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Klinakis
mesh_terms: D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D016147:Genes, Tumor Suppressor; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D009154:Mutation; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; D054637:Dual-Specificity Phosphatases