title: Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases.
abstract: Little is known about the regulation and function of the Notch1 gene in negative control of human tumors. Here we show that Notch1 gene expression and activity are substantially down-modulated in keratinocyte cancer cell lines and tumors, with expression of this gene being under p53 control in these cells. Genetic suppression of Notch signaling in primary human keratinocytes is sufficient, together with activated ras, to cause aggressive squamous cell carcinoma formation. Similar tumor-promoting effects are also caused by in vivo treatment of mice, grafted with keratinocytes expressing oncogenic ras alone, with a pharmacological inhibitor of endogenous Notch signaling. These effects are linked with a lesser commitment of keratinocytes to differentiation, an expansion of stem cell populations, and a mechanism involving up-regulation of ROCK1/2 and MRCKalpha kinases, two key effectors of small Rho GTPases previously implicated in neoplastic progression. Thus, the Notch1 gene is a p53 target with a role in human tumor suppression through negative regulation of Rho effectors.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
authors.forename: Karine
authors.initials: K
authors.lastname: Lefort
authors.forename: Anna
authors.initials: A
authors.lastname: Mandinova
authors.forename: Paola
authors.initials: P
authors.lastname: Ostano
authors.forename: Vihren
authors.initials: V
authors.lastname: Kolev
authors.forename: Valerie
authors.initials: V
authors.lastname: Calpini
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kolfschoten
authors.forename: Vikram
authors.initials: V
authors.lastname: Devgan
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Lieb
authors.forename: Wassim
authors.initials: W
authors.lastname: Raffoul
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.forename: Victor
authors.initials: V
authors.lastname: Neel
authors.forename: Jonathan
authors.initials: J
authors.lastname: Garlick
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
authors.forename: G Paolo
authors.initials: GP
authors.lastname: Dotto
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000166:cytology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C105518:CDC42BPA protein, human; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; C515851:ROCK1 protein, human; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases