Apoptosis and cell cycle regulation in a basal model system : insights from the placozoan Trichoplax adhaerens

Abstract

Complex gene networks regulated by master control genes are critical for the coordination of fundamental molecular and cellular processes in metazoans. Their misfunction might cause severe diseases like cancer. In this thesis, two evolutionary highly conserved master control genes, namely p53 and Myc, have been comprehensively analyzed in the simple metazoan model system Trichoplax adhaerens (phylum Placozoa). Additionally, the newly described species, Polyplacotoma mediterranea, will provide further promising possibilities for functional and comparative studies. The tumor suppressor p53 is well known for the regulation of programmed cell death (apoptosis), but also controls the cell metabolism and cell cycle. In this work, functional and comparative genetic studies on the p53 homolog tap53 have been performed in T. adhaerens. The in vivo accumulation of tap53 by inhibiting the tap53-taMdm2 interaction as well as the tap53 knockdown resulted in a significant increase of apoptotic cells and an increased mortality. Furthermore, multiple tap53 interaction partners identified by transcriptomic analyses after tap53 knockdown suggest the existence of an alternative and tap53-independent apoptosis signaling pathway. Genes belonging to the innate immune system and the cellular stress response were likewise found differentially expressed in response to tap53 knockdown. These results suggest that tap53 fulfills multiple crucial functions in Trichoplax and is essential for the survival of the organism. As transcription factors, Myc and its most important interaction partner Max regulate cellular processes and mechanisms such as differentiation, proliferation and the cell cycle. The biochemical studies carried out in the course of this thesis on the full-length proteins taMyc and taMax of T. adhaerens provided first insight on their protein structure and interaction. Using different methods, dimerization of full-length proteins was demonstrated which is a prerequisite for functional DNA binding capabilities. This suggests that taMyc and taMax play an essential role as transcription factors in Trichoplax and support an evolutionary conserved function throughout metazoans. This thesis provides new important insights on the function and characteristics of p53 and Myc/Max regulatory networks in a simple metazoan and is the base for future applied medical research on cellular regulation processes.