MDM2 suppresses c-Myc synthesis by binding to the 5’ mRNA translation regulatory sequence
Abstract
The p53 tumor suppressor and the c-Myc oncogene are among the most frequently deregulated genes in human cancers, yet the molecular cross talk between these pathways remains poorly understood. MDM2 is a key negative regulator of p53 and a target for emerging cancer therapies designed to activate p53. Likewise, targeting c-Myc is a long-standing but challenging goal in cancer therapy. Here, we report that the small MDM2-binding drug Milademetan promotes an interaction between MDM2 and the 5’ untranslated region of the c-Myc mRNA, causing a suppression of c-Myc mRNA translation without affecting c-Myc RNA levels. The interaction also occurs under nonproliferative conditions in the absence of drug. Milademetan-mediated c-Myc depletion is accompanied by the induction of apoptosis and suppression of cell proliferation and prevents tumor growth, independently of p53 status. These findings reveal an unexpected mechanism by which MDM2 coordinates two of the most frequently altered pathways in cancer and provide a rationale for targeting c-Myc-driven tumors, including those lacking functional p53, through MDM2 modulators.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Justine Habault
Institut de Recherche Saint Louis, Unité Mixte de Recherches 1342, Université Paris Cité, Hôpital St. Louis
Norman Salomao
Institut de Recherche Saint Louis, Unité Mixte de Recherches 1342, Université Paris Cité, Hôpital St. Louis
Lixiao Wang
Department of Medical Biosciences, Umeå University
Laurence Malbert-Colas
Institut de Recherche Saint Louis, Unité Mixte de Recherches 1342, Université Paris Cité, Hôpital St. Louis
Chrysoula Daskalogianni
Institut de Recherche Saint Louis, Unité Mixte de Recherches 1342, Université Paris Cité, Hôpital St. Louis
Sivakumar Vadivel Gnanasundram
Department of Medical Biosciences, Umeå University
Mitesh Dongre
Department of Diagnostics and Intervention, Umeå University
Marzia Spagnardi
Department of Urology, New York University Grossman School of Medicine
Lucia Martinkova
Research Center for Applied Molecular Oncology, Masaryk Memorial Cancer Institute
Sa Chen
Department of Medical Biosciences, Umeå University
Lenka Hernychová
Research Center for Applied Molecular Oncology, Masaryk Memorial Cancer Institute
Lucas Robidas
Institut de Recherche Saint Louis, Unité Mixte de Recherches 1342, Université Paris Cité, Hôpital St. Louis
Josef Kucera
Research Center for Applied Molecular Oncology, Masaryk Memorial Cancer Institute
Ondřej Bonczek
Research Center for Applied Molecular Oncology, Masaryk Memorial Cancer Institute
Daniel Öhlund
Department of Diagnostics and Intervention, Umeå University
Michael J. Garabedian
Department of Urology, New York University Grossman School of Medicine
Susan K. Logan
Department of Urology, New York University Grossman School of Medicine
Borek Vojtesek
Research Center for Applied Molecular Oncology, Masaryk Memorial Cancer Institute
Robin Fahraeus
Institut de Recherche Saint Louis, Unité Mixte de Recherches 1342, Université Paris Cité, Hôpital St. Louis