Thesis (Ph. D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Pathology and Laboratory Medicine, 2008.
SUMO-specific protease 2 (SENP2) modifies proteins by removing SUMO from its substrates. Although SUMO-specific proteases are known to reverse sumoylation in many defined systems, their importance in mammalian development and pathogenesis remains largely elusive. In this thesis, I demonstrate that SENP2 is highly expressed in trophoblasts that are required for placentation. Targeted disruption of SENP2 in mice reveals its essential role in development of all three trophoblast layers. In the labyrinth layer, the mutation causes defects in formation of maternal and fetal blood spaces. In spongiotrophoblast and trophoblast giant cell layers, there are deficiencies in cell cycle progression induced by the SENP2-null. SENP2 has a specific role in the G1/S transition required for mitotic and endoreduplication cell cycles in trophoblast proliferation and differentiation, respectively. The ablation of SENP2 disrupts the p53/MDM2 pathway, affecting the expansion of stem cells and the maturation of trophoblasts. Reintroducing SENP2 into the mutants can reduce the sumoylation of MDM2, diminish the level of p53 and promote trophoblast development. Furthermore, down regulation of p53 alleviates the SENP2-null phenotypes and stimulation of p53 causes abnormalities in trophoblast proliferation and differentiation, resembling those of the SENP2 mutant. This study reveals a key genetic pathway of SENP2-MDM2-p53 underlying trophoblast lineage development, suggesting its pivotal role in cell cycle progression of mitosis and endoreduplication.
