title: SKP2 is a direct transcriptional target of MYCN and a potential therapeutic target in neuroblastoma.
abstract: SKP2 is the substrate recognition subunit of the ubiquitin ligase complex which targets p27(KIP1) for degradation. Induced at the G1/S transit of the cell cycle, SKP2 is frequently overexpressed in human cancers and contributes to malignancy. We previously identified SKP2 as a possible MYCN target gene and hence hypothesise that SKP2 is a potential therapeutic target in MYCN amplified disease. A positive correlation was identified between MYCN activity and SKP2 mRNA expression in Tet21N MYCN-regulatable cells and a panel of MYCN amplified and non-amplified neuroblastoma cell lines. In chromatin immunoprecipitation and reporter gene assays, MYCN bound directly to E-boxes within the SKP2 promoter and induced transcriptional activity which was decreased by the removal of MYCN and E-box mutation. Although SKP2 knockdown inhibited cell growth in both MYCN amplified and non-amplified cells, cell cycle arrest and apoptosis were induced only in non-MYCN amplified neuroblastoma cells. In conclusion these data identify SKP2 as a direct transcriptional target of MYCN and supports SKP2 as a potential therapeutic target in neuroblastoma.
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Evans
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: Lindi
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via F. Selmi 3, Bologna 40126, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Milazzo
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via F. Selmi 3, Bologna 40126, Italy; Health Science and Technologies-Interdepartmental Centre for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, Ozzano Emilia (Bologna) 40064, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Gherardi
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via F. Selmi 3, Bologna 40126, Italy; Health Science and Technologies-Interdepartmental Centre for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, Ozzano Emilia (Bologna) 40064, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Willmore
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK. Electronic address: deborah.tweddle@newcastle.ac.uk.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Tweddle
mesh_terms: D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D024721:E-Box Elements; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins
keywords: Apoptosis; G(1) arrest; MYCN; Neuroblastoma; SKP2