SUMO-specific protease 2 is essential for modulating p53-Mdm2 in development of trophoblast stem cell niches and lineages.
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. Here we report that SENP2 is highly expressed in trophoblast cells that are required for placentation. Targeted disruption of SENP2 in mice reveals its essential role in development of all three trophoblast layers. The mutation causes a deficiency in cell cycle progression. SENP2 has a specific role in the G-S transition, which is required for mitotic and endoreduplication cell cycles in trophoblast proliferation and differentiation, respectively. SENP2 ablation disturbs the p53-Mdm2 pathway, affecting the expansion of trophoblast progenitors and their maturation. Reintroducing SENP2 into the mutants can reduce the sumoylation of Mdm2, diminish the p53 level and promote trophoblast development. Furthermore, downregulation of p53 alleviates the SENP2-null phenotypes and stimulation of p53 causes abnormalities in trophoblast proliferation and differentiation, resembling those of the SENP2 mutants. Our data reveal a key genetic pathway, SENP2-Mdm2-p53, underlying trophoblast lineage development, suggesting its pivotal role in cell cycle progression of mitosis and endoreduplication.
Chiu
Shang-Yi
SY
Department of Biomedical Genetics, Center for Oral Biology, James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA.
Asai
Naoya
N
Costantini
Frank
F
Hsu
Wei
W
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D019070:Cell Lineage; D003546:Cysteine Endopeptidases; D004622:Embryo, Mammalian / Q000187:drug effects / Q000196:embryology; D053595:Embryonic Stem Cells / Q000502:physiology; D051379:Mice; D009097:Multienzyme Complexes / Q000172:deficiency / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D014327:Trophoblasts / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D009097:Multienzyme Complexes; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D003546:Cysteine Endopeptidases; C439066:Senp2 protein, mouse