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MDM2 suppresses c-Myc synthesis by binding to the 5' mRNA translation regulatory sequence

Justine Habault1, Norman Salomao1, Lixiao Wang2

  • 1Institut de Recherche Saint Louis, Unité Mixte de Recherches 1342, Université Paris Cité, Hôpital St. Louis, Paris 75010, France.

Proceedings of the National Academy of Sciences of the United States of America
|June 23, 2026
PubMed

Insights

The drug Milademetan links MDM2 to c-Myc mRNA, suppressing c-Myc translation and tumor growth. This cancer therapy approach works independently of p53 status.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • p53 tumor suppressor and c-Myc oncogene are frequently deregulated in human cancers.
  • Molecular cross talk between p53 and c-Myc pathways is poorly understood.
  • MDM2 is a key negative regulator of p53 and a therapeutic target; c-Myc targeting is challenging.

Purpose of the Study:

  • To investigate the molecular cross talk between p53 and c-Myc pathways.
  • To explore the mechanism of action of the MDM2-binding drug Milademetan.
  • To determine the therapeutic potential of targeting c-Myc via MDM2 modulation.

Main Methods:

  • Utilized Milademetan, a small MDM2-binding drug.
  • Investigated the interaction between MDM2 and c-Myc mRNA.
  • Assessed effects on c-Myc mRNA translation, protein levels, apoptosis, cell proliferation, and tumor growth.
  • Evaluated outcomes independently of p53 status.

Main Results:

  • Milademetan promotes MDM2 interaction with the 5' untranslated region of c-Myc mRNA.
  • This interaction suppresses c-Myc mRNA translation without affecting RNA levels.
  • Milademetan-induced c-Myc depletion leads to apoptosis, suppressed proliferation, and prevented tumor growth.
  • The observed effects are independent of p53 status.

Conclusions:

  • MDM2 plays an unexpected role in coordinating p53 and c-Myc pathways in cancer.
  • MDM2 modulators can suppress c-Myc translation and inhibit tumor growth.
  • Targeting c-Myc-driven tumors, including those with non-functional p53, via MDM2 modulators is a viable therapeutic strategy.
Keywords:
MDM2-RNA interactionc-MYCp53translation controltumor heterogeneity

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