title: SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.
abstract: The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanisms converting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 by phosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced the transcription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to Myc Box I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activated protein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Myc protein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 down-regulated, in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis in TH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors in the prevention and therapy of N-Myc-induced neuroblastoma.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.forename: Pei Y
authors.initials: PY
authors.lastname: Liu
authors.forename: Samuele
authors.initials: S
authors.lastname: Gherardi
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scarlett
authors.forename: Antonio
authors.initials: A
authors.lastname: Bedalov
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.forename: Nuncio
authors.initials: N
authors.lastname: Iraci
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valli
authors.forename: Dora
authors.initials: D
authors.lastname: Ling
authors.forename: Wayne
authors.initials: W
authors.lastname: Thomas
authors.forename: Margo
authors.initials: M
authors.lastname: van Bekkum
authors.forename: Eric
authors.initials: E
authors.lastname: Sekyere
authors.forename: Kacper
authors.initials: K
authors.lastname: Jankowski
authors.forename: Toby
authors.initials: T
authors.lastname: Trahair
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mackenzie
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008822:Mice, Transgenic; D009281:Naphthalenes / Q000494:pharmacology; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011744:Pyrimidinones / Q000494:pharmacology; D011897:Random Allocation; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D009281:Naphthalenes; D016271:Proto-Oncogene Proteins c-myc; D011744:Pyrimidinones; D016329:Sp1 Transcription Factor; C510718:cambinol; D048049:Extracellular Signal-Regulated MAP Kinases; D054642:Dual Specificity Phosphatase 6; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1