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 feedba...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-06-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3116909?pdf=render |
| _version_ | 1818015696131457024 |
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| author | Glenn M Marshall Pei Y Liu Samuele Gherardi Christopher J Scarlett Antonio Bedalov Ning Xu Nuncio Iraci Emanuele Valli Dora Ling Wayne Thomas Margo van Bekkum Eric Sekyere Kacper Jankowski Toby Trahair Karen L Mackenzie Michelle Haber Murray D Norris Andrew V Biankin Giovanni Perini Tao Liu |
| author_facet | Glenn M Marshall Pei Y Liu Samuele Gherardi Christopher J Scarlett Antonio Bedalov Ning Xu Nuncio Iraci Emanuele Valli Dora Ling Wayne Thomas Margo van Bekkum Eric Sekyere Kacper Jankowski Toby Trahair Karen L Mackenzie Michelle Haber Murray D Norris Andrew V Biankin Giovanni Perini Tao Liu |
| author_sort | Glenn M Marshall |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:01:19Z |
| format | Article |
| id | doaj.art-540a116698744d01b5e6204be81788da |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-14T07:01:19Z |
| publishDate | 2011-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-540a116698744d01b5e6204be81788da2022-12-22T02:06:45ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-06-0176e100213510.1371/journal.pgen.1002135SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.Glenn M MarshallPei Y LiuSamuele GherardiChristopher J ScarlettAntonio BedalovNing XuNuncio IraciEmanuele ValliDora LingWayne ThomasMargo van BekkumEric SekyereKacper JankowskiToby TrahairKaren L MackenzieMichelle HaberMurray D NorrisAndrew V BiankinGiovanni PeriniTao LiuThe 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.http://europepmc.org/articles/PMC3116909?pdf=render |
| spellingShingle | Glenn M Marshall Pei Y Liu Samuele Gherardi Christopher J Scarlett Antonio Bedalov Ning Xu Nuncio Iraci Emanuele Valli Dora Ling Wayne Thomas Margo van Bekkum Eric Sekyere Kacper Jankowski Toby Trahair Karen L Mackenzie Michelle Haber Murray D Norris Andrew V Biankin Giovanni Perini Tao Liu SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. PLoS Genetics |
| title | SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. |
| title_full | SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. |
| title_fullStr | SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. |
| title_full_unstemmed | SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. |
| title_short | SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. |
| title_sort | sirt1 promotes n myc oncogenesis through a positive feedback loop involving the effects of mkp3 and erk on n myc protein stability |
| url | http://europepmc.org/articles/PMC3116909?pdf=render |
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