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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.

ISBN 1553-7390 (Linking)
Authors Marshall, G.M.; Liu, P.; Gherardi, S.; Scarlett, C.; Bedalov, A.; Xu, N.; Iraci, N.; Valli, E.; Ling, D.; Thomas, W.; Van Bekkum, M.; Sekyere, E.; Jankowski, K.; Trahair, T.; MacKenzie, K.L.; Haber, M.; Norris, M.; Biankin, A.V.; Perini, G.; Liu, T.
Publisher Name PLOS GENET
Published Date 2011-07-01
Published Volume 7
Published Issue 6
Published Pages e1002135
Status Published in-print
DOI 10.1371/journal.pgen.1002135 PGENETICS-D-10-00535 [pii]
URL link to publisher's version
OpenAccess link to author's accepted manuscript version