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The alternative translated MDMX(p60) isoform regulates MDM2 activity
Anne-Sophie Tournillon1, Ignacio López, Laurence Malbert-Colas
1a Cibles Thérapeutiques, Equipe Labellisée la Ligue Contre le Cancer, Institut National de la Santé et de la Recherche Médicale UMR1162; Institut de Génétique Moléculaire , Université Paris 7 ; Hôpital St. Louis; Paris , France.
Cell Cycle (Georgetown, Tex.)
|February 7, 2015
Summary
A novel human MDMX (hMDMX) isoform, hMDMX(p60), is generated via cap-independent translation. This isoform uniquely regulates MDM2 activity and protein stability, impacting the p53 family signaling pathway.
Area of Science:
- Molecular Biology
- Cancer Biology
- Protein Regulation
Background:
- Alternative splicing and translation initiation generate diverse protein isoforms.
- The p53 family, including p53, p63, and p73, plays critical roles in cellular responses.
- MDM2 and MDMX are key negative regulators of p53.
Purpose of the Study:
- To investigate the functional consequences of alternative translation initiation of the hMDMX gene.
- To characterize a novel N-terminal truncated isoform of hMDMX, termed hMDMX(p60).
- To elucidate the regulatory role of hMDMX(p60) in the MDM2-MDMX interaction and function.
Main Methods:
- Cap-independent translation assays to identify and characterize hMDMX(p60).
- Co-immunoprecipitation to study protein-protein interactions (hMDMX(p60), hMDM2, hMDMX(FL)).
- In vitro binding assays to determine binding affinities.
- Cellular assays (in cellulo) to assess protein stability and degradation pathways.
Main Results:
- Identified hMDMX(p60) generated by cap-independent translation initiating at the 7th AUG codon.
- hMDMX(p60) lacks the p53 binding motif but retains the RING domain and interacts with hMDM2 and hMDMX(FL).
- hMDMX(p60) exhibits higher affinity for hMDM2 than hMDMX(FL), cooperates with hMDM2, and differentially regulates hMDM2 and hMDMX(FL) stability based on its concentration.
Conclusions:
- A novel alternatively translated hMDMX isoform, hMDMX(p60), has been described.
- hMDMX(p60) possesses unique regulatory functions over hMDM2 autoubiquitination and protein stability.
- The N-terminus of hMDMX plays a crucial role in modulating its C-terminal RING domain activity and interaction with hMDM2.
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