The p53 tumor suppressor and its key regulator MDM2 play essential roles in development, ageing, cancer, and cellular stress responses in mammals. Following DNA damage, MDM2 interacts with p53 mRNA in an ATM kinase-dependent fashion and stimulates p53 synthesis, whereas under normal conditions, MDM2 targets the p53 protein for degradation. The peptide- and RNA motifs that interact with MDM2 are encoded by the same conserved BOX-I sequence, but how these interactions have evolved is unknown. Here, we show that a temperature-sensitive structure in the invertebrate Ciona intestinalis (Ci) p53 mRNA controls its interaction with MDM2. We also show that a nonconserved flanking region of Ci-BOX-I domain prevents the p53-MDM2 protein-protein interaction. These results indicate that the temperature-regulated p53 mRNA-MDM2 interaction evolved to become kinase regulated in the mammalian DNA damage response. The data also suggest that the negative regulation of p53 by MDM2 via protein-protein interaction evolved in vertebrates following changes in the BOX-I flanking sequence.

Department of Medical Biosciences Umeå University Umeå Sweden

Edinburgh Cancer Research UK Centre the University of Edinburgh Edinburgh United Kingdom

Équipe Labellisée Ligue Contre le Cancer Université Paris 7 INSERM UMR 1162 Paris France

Équipe Labellisée Ligue Contre le Cancer Université Paris 7 INSERM UMR 1162 Paris France Regional Centre for Applied Molecular Oncology RECAMO and Masaryk Memorial Cancer Institute Brno Czech Republic Department of Medical Biosciences Umeå University Umeå Sweden

Regional Centre for Applied Molecular Oncology RECAMO and Masaryk Memorial Cancer Institute Brno Czech Republic

UPMC CNRS FR2424 Station Biologique de Roscoff Roscoff France

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