title: Negative control of CSL gene transcription by stress/DNA damage response and p53.
abstract: CSL is a key transcriptional repressor and mediator of Notch signaling. Despite wide interest in CSL, mechanisms responsible for its own regulation are little studied. CSL down-modulation in human dermal fibroblasts (HDFs) leads to conversion into cancer associated fibroblasts (CAF), promoting keratinocyte tumors. We show here that CSL transcript levels differ among HDF strains from different individuals, with negative correlation with genes involved in DNA damage/repair. CSL expression is negatively regulated by stress/DNA damage caused by UVA, Reactive Oxygen Species (ROS), smoke extract, and doxorubicin treatment. P53, a key effector of the DNA damage response, negatively controls CSL gene transcription, through suppression of CSL promoter activity and, indirectly, by increased p21 expression. CSL was previously shown to bind p53 suppressing its activity. The present findings indicate that p53, in turn, decreases CSL expression, which can serve to enhance p53 activity in acute DNA damage response of cells.
authors.affiliation: a Department of Biochemistry , University of Lausanne , Epalinges , Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Menietti
authors.affiliation: a Department of Biochemistry , University of Lausanne , Epalinges , Switzerland.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Xu
authors.affiliation: b Cancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation , Biella , Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ostano
authors.affiliation: c Pediatric surgery Department , University Hospital CHUV , Lausanne , Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Joseph
authors.affiliation: a Department of Biochemistry , University of Lausanne , Epalinges , Switzerland.|d Department of Dermatology , University Hospital CHUV , Lausanne , Switzerland.
authors.forename: Karine
authors.initials: K
authors.lastname: Lefort
authors.affiliation: a Department of Biochemistry , University of Lausanne , Epalinges , Switzerland.|e Cutaneous Biology Research Center, Massachusetts General Hospital , Charlestown , MA , USA.
authors.forename: G Paolo
authors.initials: GP
authors.lastname: Dotto
mesh_terms: D002460:Cell Line; D004249:DNA Damage / Q000235:genetics*; D020405:Dermis / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009153:Mutagens / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009153:Mutagens; C497570:RBPJ protein, human; D051880:Receptors, Notch; D016159:Tumor Suppressor Protein p53
keywords: CSL/RBPJκ; UVA/DNA damage response; dermal fibroblasts; individual variations in gene transcription; p53