title: Loss of Notch1-dependent p21(Waf1/Cip1) expression influences the Notch1 outcome in tumorigenesis.
abstract: Notch signaling plays a complex role in carcinogenesis, and its signaling pathway has both tumor-suppressor and oncogenic components. In this study we investigated the effects of reactive oxygen species (ROS) on Notch1 signaling outcome in keratinocyte biology. We demonstrate that Notch1 function contributes to the arsenic-induced keratinocyte transformation. We found that acute exposure to arsenite increases oxidative stress and inhibits proliferation of keratinocyte cells by upregulation of p21(waf1/Cip1). The necessity of p21(waf1/Cip1) for arsenite-induced cell death was demonstrated by targeted downregulation of p21(waf1/Cip1) by using RNA interference. We further demonstrated that on acute exposure to arsenite, p21(waf1/Cip1) is upregulated and Notch1 downmodulated, whereas on chronic exposure to arsenite, malignant progression of arsenite-treated keratinocytes cells was accompanied by regained expression and activity of Notch1. Notch1 activity in arsenite-transformed keratinocytes inhibits arsenite-induced upregulation of p21(waf1/Cip1) by sustaining c-myc expression. We further demonstrated that c-myc collaborates with Nrf2, a key regulator for the maintenance of redox homeostasis, to promote metabolic activities that support cell proliferation and cytoprotection. Therefore, Notch1-mediated repression of p21(waf1/Cip1) expression results in the inhibition of cell death and keratinocytes transformation. Our results not only demonstrate that sustained Notch1 expression is at least one key event implicated in the arsenite human skin carcinogenic effect, but also may provide mechanistic insights into the molecular aspects that determine whether Notch signaling will be either oncogenic or tumor suppressive.
authors.affiliation: Department of Molecular Medicine; Sapienza University of Rome; Rome, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Cialfi
authors.affiliation: Center for Life Nanosciences at Sapienza; Istituto Italiano di Tecnologia; Rome, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Palermo
authors.affiliation: Department of Molecular Medicine; Sapienza University of Rome; Rome, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Manca
authors.affiliation: Department of Molecular Medicine; Sapienza University of Rome; Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: De Blasio
authors.affiliation: Department of Molecular Medicine; Sapienza University of Rome; Rome, Italy.
authors.forename: Paula
authors.initials: P
authors.lastname: Vargas Romero
authors.affiliation: Department of Biotechnology and Medical-Surgical Sciences; Sapienza University; Latina, Italy.
authors.forename: Saula
authors.initials: S
authors.lastname: Checquolo
authors.affiliation: Department of Molecular Medicine; Sapienza University of Rome; Rome, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Bellavia
authors.affiliation: Department of Biology and Biotechnology "C. Darwin"; Sapienza University of Rome; Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Uccelletti
authors.affiliation: Department of Biology and Biotechnology "C. Darwin"; Sapienza University of Rome; Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Saliola
authors.affiliation: Department of Ecological and Biological Sciences; University of Tuscia; Viterbo, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: Department of Ecological and Biological Sciences; University of Tuscia; Viterbo, Italy.
authors.forename: Lello
authors.initials: L
authors.lastname: Zolla
authors.affiliation: Department of Molecular Medicine; Sapienza University of Rome; Rome, Italy; Center for Life Nanosciences at Sapienza; Istituto Italiano di Tecnologia; Rome, Italy; Neuromed Institute; Pozzilli, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Department of Molecular Medicine; Sapienza University of Rome; Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Molecular Medicine; Sapienza University of Rome; Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Talora
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000633:toxicity; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018053:Arsenites; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases; C493956:CDKN1A protein, human; C513273:FBXW7 protein, human; C525067:MIR223, human; C489427:MYC protein, human; C495635:NFE2L2 protein, human; C497761:NOTCH1 protein, human; C015001:arsenite
keywords: Notch; Nrf2; metabolism; p21