The tumor suppressor p53 plays a crucial role in apoptosis and cell cycle regulation and ensures a cell’s integrity [1, 2]. Endogenous p53 levels are regulated by the ubiquitin ligase Mdm2 [3]. Both p53 and Mdm2 have been shown to be conserved throughout the animal kingdom and orthologs of both genes have been found in the simplest animal, Trichoplax adhaerens [4, 5, 6]. Our first studies have shown that the interplay is crucial for the animals’ health and chemical interruption of the p53/Mdm2 interaction leads to abnormal phenotypes.

Roscovitine 15 800  Roscovitine 17 800

Artificially induced cancer and tumor-like growth in Trichoplax adhaerens.

We also seek to better understand the interplay between Myc and Max in Trichoplax. Myc is a proto-oncogene and its malfunction leads to an enhanced formation of tumors [7, 8] As a transcription factor belonging to a family of bHLH-Zip proteins, Myc interacts with Max and several other proteins to activate or repress downstream target genes [9, 10]. Myc and Max are conserved within the Metazoa [11, 12] and are of fundamental importance for cellular processes. Within the diploblasts, research on these transcription factors has mainly been conducted on the freshwater polyp Hydra [13, 14]. To elucidate their functions we use functional genetics combined with biochemical and biophysical approaches.

Alpha tubulin and DAPI staining in Trichoplax adhaerens.
The bar marks 50 µm.

References:
[1] Levine AJ, Oren M (2009) The first 30 years of p53: growing ever more
complex. Nat Rev Cancer 9(10):749–758

[2] Vousden KH, Prives C (2009) Blinded by the light: the growing complexity
of p53. Cell 137(3):413–431

[3] 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

[4] 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

[5] 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

[6] Chevallerie vd, K, Rolfes, S, Schierwater, B (2014) 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

[7] Meyer N, Penn LZ (2008) Reflecting on 25 years with MYC. Nat Rev Cancer 8, 976-990

[8] Sheiness D, Fanshier L, Bishop JM (1978) Identification of nucleotide sequences which may encode the oncogenic capacity of avian retrovirus MC29. J Virol 28, 600-610

[9] Grandori C, Eisenman RN (1997) Myc target genes. Trends Biochem Sci 22, 177-181

[10] Blackwell TK, Kretzner L, Blackwood EM, Eisenman RN, Weintraub H (1990) Sequence-specific DNA binding by the c-Myc protein. Science 250, 1149-1151

[11] Sebe-Pedros A, de Mendoza A, Lang BF, Degnan BM, Ruiz-Trillo I (2011) Unexpected repertoire of metazoan transcription factors in the unicellular holozoan Capsaspora owczarzaki. Mol Biol Evol 28, 1241-1254

[12] King N, Westbrook MJ, Young SL, Kuo A, Abedin M, Chapman J, Fairclough S, Hellsten U, Isogai Y, Letunic I, et al. (2008) The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans. Nature 451, 783-788

[13] Hartl M, Mitterstiller AM, Valovka T, Breuker K, Hobmayer B, Bister K (2010) Stem cell-specific activation of an ancestral myc protooncogene with conserved basic functions in the early metazoan Hydra. Proc Natl Acad Sci U S A. 2010 Mar 2; 107(9): 4051–4056
[14] Hartl M, Glasauer S, Valovka T, Breuker K, Hobmayer B, Bister K (2014) Hydra myc2, a unique pre-bilaterian member of the myc gene family, is activated in cell proliferation and gametogenesis. Biology Open (2014) 000, 1–11

 

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