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Related Experiment Video

Updated: May 31, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

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

Glenn M Marshall¹, Pei Y Liu, Samuele Gherardi

¹Children's Cancer Institute Australia for Medical Research, Randwick, Australia.

|June 24, 2011

Summary

Neuroblastoma tumorigenesis involves N-Myc oncoprotein stabilization. A newly discovered feedback loop shows SIRT1 enhances N-Myc stability, offering potential therapeutic targets for neuroblastoma prevention and treatment.

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Last Updated: May 31, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

Area of Science:

Oncology
Molecular Biology
Gene Regulation

Background:

N-Myc oncoprotein drives neuroblastoma, but requires mechanisms for high expression.
N-Myc protein stability is regulated by phosphorylation, notably at Serine 62 by ERK.
Understanding N-Myc regulation is crucial for neuroblastoma therapy.

Purpose of the Study:

To elucidate a novel positive feedback loop involving N-Myc and SIRT1 in neuroblastoma.
To investigate the role of SIRT1 in N-Myc protein stabilization.
To evaluate SIRT1 inhibitors as a therapeutic strategy for N-Myc-induced neuroblastoma.

Main Methods:

Investigated the transcriptional regulation of SIRT1 by N-Myc.
Assessed the interaction between SIRT1 and N-Myc.
Analyzed the effect of SIRT1 on MKP3 gene expression and ERK phosphorylation.
Utilized TH-MYCN transgenic mice for in vivo studies.

Main Results:

N-Myc directly induces SIRT1 transcription, creating a positive feedback loop.
SIRT1 binds to N-Myc, forming a repressor complex at the MKP3 promoter, decreasing MKP3 expression.
This leads to increased ERK phosphorylation, subsequent N-Myc phosphorylation at Serine 62, and enhanced N-Myc protein stability.
SIRT1 was upregulated and MKP3 downregulated in pre-cancerous cells.
SIRT1 inhibition with Cambinol reduced tumorigenesis in TH-MYCN mice.

Conclusions:

SIRT1 plays a critical role in N-Myc oncogenesis by stabilizing N-Myc protein.
The identified SIRT1-N-Myc feedback loop is a key driver of neuroblastoma development.
SIRT1 inhibitors show promise for the prevention and therapy of N-Myc-driven neuroblastoma.