SIRT1 Promotes N-Myc Oncogenesis through a Positive Feedback Loop Involving the Effects of MKP3 and ERK on N-Myc Protein Stability.

Marshall, G. M.; Liu, P. Y.; Gherardi, S.; Scarlett, C. J.; Bedalov, A.; Xu, N.; Iraci, Nunzio; Valli, E.; Ling, D.; Thomas, W.; van Bekkum, M.; Sekyere, E.; Jankowski, K.; Trahair, T.; Mackenzie, K. L.; Haber, M.; Norris, M. D.; Biankin, A. V.; Perini, G.; T. L. i. u.,

doi:10.1371/journal.pgen.1002135

The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanismsconverting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 byphosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced thetranscription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to MycBox I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activatedprotein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Mycprotein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 downregulated,in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis inTH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors inthe prevention and therapy of N-Myc–induced neuroblastoma.

Titolo:	SIRT1 Promotes N-Myc Oncogenesis through a Positive Feedback Loop Involving the Effects of MKP3 and ERK on N-Myc Protein Stability.
Autori interni:	G. M. Marshall P. Y. Liu S. Gherardi C. J. Scarlett A. Bedalov N. Xu IRACI, NUNZIO E. Valli D. Ling W. Thomas M. van Bekkum E. Sekyere K. Jankowski T. Trahair K. L. Mackenzie M. Haber M. D. Norris A. V. Biankin G. Perini T. L.i.u. mostra contributor esterni nascondi contributor esterni
Data di pubblicazione:	2011
Rivista:	PLOS GENETICS
Abstract:	The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanismsconverting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 byphosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced thetranscription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to MycBox I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activatedprotein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Mycprotein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 downregulated,in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis inTH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors inthe prevention and therapy of N-Myc–induced neuroblastoma.
Handle:	http://hdl.handle.net/20.500.11769/243588
Appare nelle tipologie:	1.1 Articolo in rivista

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