Abstract
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.
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References
Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP (2009) Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 9(12):862–873. doi:10.1038/nrc2763
de Jong D, Eitel M, Jakob W, Osigus HJ, Hadrys H, DeSalle R, Schierwater B (2009) Multiple dicer genes in the early-diverging metazoa. Mol Biol Evol 26(6):1333–1340. doi:10.1093/molbev/msp042
Derry WB, Putzke AP, Rothman JH (2001) Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294(5542):591–595. doi:10.1126/science.1065486
Eitel M, Osigus HJ, DeSalle R, Schierwater B (2013) Global diversity of the Placozoa. PLoS One 8(4):e57131. doi:10.1371/journal.pone.0057131
Jakob W, Sagasser S, Dellaporta S, Holland P, Kuhn K, Schierwater B (2004) The Trox-2 Hox/ParaHox gene of Trichoplax (Placozoa) marks an epithelial boundary. Dev Genes Evol 214(4):170–175. doi:10.1007/s00427-004-0390-8
Jessen-Eller K, Kreiling JA, Begley GS, Steele ME, Walker CW, Stephens RE, Reinisch CL (2002) A new invertebrate member of the p53 gene family is developmentally expressed and responds to polychlorinated biphenyls. Environ Health Perspect 110(4):377–385
Jin S, Martinek S, Joo WS, Wortman JR, Mirkovic N, Sali A, Yandell MD, Pavletich NP, Young MW, Levine AJ (2000) Identification and characterization of a p53 homologue in Drosophila melanogaster. Proc Natl Acad Sci U S A 97(13):7301–7306
Joerger AC, Fersht AR (2007) Structure-function-rescue: the diverse nature of common p53 cancer mutants. Oncogene 26(15):2226–2242. doi:10.1038/sj.onc.1210291
Lane DP, Verma C (2012) Mdm2 in evolution. Genes Cancer 3(3–4):320–324. doi:10.1177/1947601912458285
Lane DP, Cheok CF, Brown C, Madhumalar A, Ghadessy FJ, Verma C (2010) Mdm2 and p53 are highly conserved from placozoans to man. Cell Cycle 9(3):540–547
Levine AJ, Oren M (2009) The first 30 years of p53: growing ever more complex. Nat Rev Cancer 9(10):749–758. doi:10.1038/nrc2723
Lu W, Chen L, Peng Y, Chen J (2001) Activation of p53 by roscovitine-mediated suppression of MDM2 expression. Oncogene 20(25):3206–3216. doi:10.1038/sj.onc.1204412
Manfredi JJ (2010) The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev 24(15):1580–1589. doi:10.1101/gad.1941710
Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, Inagaki M, Delcros JG, Moulinoux JP (1997) Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem 243(1–2):527–536
Momand J, Villegas A, Belyi VA (2011) The evolution of MDM2 family genes. Gene 486(1–2):23–30. doi:10.1016/j.gene.2011.06.030
Muttray AF, O'Toole TF, Morrill W, Van Beneden RJ, Baldwin SA (2010) An invertebrate mdm homolog interacts with p53 and is differentially expressed together with p53 and ras in neoplastic Mytilus trossulus haemocytes. Comp Biochem Physiol B Biochem Mol Biol 156(4):298–308. doi:10.1016/j.cbpb.2010.04.008
Osigus HJ, Eitel M, Schierwater B (2013) Chasing the urmetazoon: striking a blow for quality data? Mol Phylogenet Evol 66(2):551–557. doi:10.1016/j.ympev.2012.05.028
Pankow S, Bamberger C (2007) The p53 tumor suppressor-like protein nvp63 mediates selective germ cell death in the sea anemone Nematostella vectensis. PLoS One 2(9):e782. doi:10.1371/journal.pone.0000782
Pearson BJ, Sanchez Alvarado A (2010) A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages. Development 137(2):213–221. doi:10.1242/dev.044297
Ringrose JH, van den Toorn HW, Eitel M, Post H, Neerincx P, Schierwater B, Maarten Altelaar AF, Heck AJ (2013) Deep proteome profiling of Trichoplax adhaerens reveals remarkable features at the origin of metazoan multicellularity. Nat Commun 4:1408. doi:10.1038/ncomms2424
Schierwater B (2005) My favorite animal, Trichoplax adhaerens. Bioessays 27(12):1294–1302. doi:10.1002/bies.20320
Schierwater B, Kuhn K (1998) Homology of Hox genes and the zootype concept in early metazoan evolution. Mol Phylogenet Evol 9(3):375–381. doi:10.1006/mpev.1998.0489
Schierwater B, de Jong D, Desalle R (2009a) Placozoa and the evolution of Metazoa and intrasomatic cell differentiation. Int J Biochem Cell Biol 41(2):370–379. doi:10.1016/j.biocel.2008.09.023
Schierwater B, Eitel M, Jakob W, Osigus HJ, Hadrys H, Dellaporta SL, Kolokotronis SO, DeSalle R (2009b) Concatenated analysis sheds light on early metazoan evolution and fuels a modern "Urmetazoon" hypothesis. Plos Biol 7(1):36–44. doi:10.1371/journal.pbio.1000020
Schwartz V (1984) The radial polar pattern of differentiation in Trichoplax adhaerens F.E. Schulze (Placozoa). Z Naturforsch 39:818–832
Srivastava M, Begovic E, Chapman J, Putnam NH, Hellsten U, Kawashima T, Kuo A, Mitros T, Salamov A, Carpenter ML, Signorovitch AY, Moreno MA, Kamm K, Grimwood J, Schmutz J, Shapiro H, Grigoriev IV, Buss LW, Schierwater B, Dellaporta SL, Rokhsar DS (2008) The Trichoplax genome and the nature of placozoans. Nature 454(7207):955–960. doi:10.1038/nature07191
Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303(5659):844–848. doi:10.1126/science.1092472
Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137(3):413–431. doi:10.1016/j.cell.2009.04.037
Acknowledgments
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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Communicated by Volker G. Hartenstein
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von der Chevallerie, K., Rolfes, S. & Schierwater, B. Inhibitors of the p53-Mdm2 interaction increase programmed cell death and produce abnormal phenotypes in the placozoon Trichoplax adhaerens (F.E. Schulze). Dev Genes Evol 224, 79–85 (2014). https://doi.org/10.1007/s00427-014-0465-0
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DOI: https://doi.org/10.1007/s00427-014-0465-0