SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.

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.
Mesh Terms:
Animals, Binding Sites, Cell Line, Tumor, Cell Proliferation, Dual Specificity Phosphatase 6, Enzyme Inhibitors, Extracellular Signal-Regulated MAP Kinases, Feedback, Physiological, Gene Expression Regulation, Neoplastic, Mice, Mice, Transgenic, Naphthalenes, Neuroblastoma, Phosphorylation, Promoter Regions, Genetic, Protein Stability, Proto-Oncogene Proteins c-myc, Pyrimidinones, Random Allocation, Sirtuin 1, Sp1 Transcription Factor, Tumor Burden
PLoS Genet.
Date: Jun. 01, 2011
Download Curated Data For This Publication
136479
Switch View:
  • Interactions 3