Inhibitors of the p53-Mdm2 interaction increase programmed cell death and produce abnormal phenotypes in the placozoon Trichoplax adhaerens (F.E. Schulze)
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Recent identification of genes homologous to human p53 and Mdm2 in the basal phylum Placozoa raised the question whether the network undertakes the same functions in the most primitive metazoan organism as it does in more derived animals. Here, we describe inhibition experiments on p53/Mdm2 interaction in Trichoplax adhaerens by applying the inhibitors nutlin-3 and roscovitine. Both inhibitors had a strong impact on the animals’ survival by significantly increasing programmed cell death (cf. apoptosis, measured via terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay). Treatment with roscovitine decreased cell proliferation (visualized by means of bromodeoxyuridine incorporation), which is likely reducible to its function as cyclin-dependent kinase inhibitor. Obvious phenotypic abnormalities have been observed during long-term application of both inhibitors, and either treatment is highly lethal in T. adhaerens. The findings of this study suggest a conserved role of the p53/Mdm2 network for programmed cell death since the origin of the Metazoa and advocate the deployment of Placozoa as a model for p53, apoptosis, and possibly cancer research.
KeywordsPlacozoa p53 Mdm2 Nutlin-3 Roscovitine
K. vdC thanks the Evangelische Studienwerk Villigst e.V. for a PhD fellowship and the Boehringer Ingelheim Fonds for a travel grant. We are grateful to Dr. Ismail M. Hanif for providing the inhibitors and for coming up with the initial idea for the experiments. We thank two anonymous reviewers for their valuable comments that improved the manuscript.
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