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.
SUMO-Specific Protease 2 Is Essential for Modulating p53-Mdm2 in Development of Trophoblast Stem Cell Niches and Lineages
Shang-Yi Chiu,N. Asai,F. Costantini,W. Hsu
Published 2008 in PLoS Biology
ABSTRACT
PUBLICATION RECORD
- Publication year
2008
- Venue
PLoS Biology
- Publication date
2008-12-01
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- cell cycle progression
The ordered advance of trophoblast cells through cell-cycle phases described in the mutant phenotype.
- endoreduplication cell cycle
A cell-cycle program in which DNA replication occurs without mitosis, relevant to trophoblast differentiation here.
Aliases: endoreduplication
- g–s transition
The transition between G phase and S phase of the cell cycle in trophoblast cells.
Aliases: G-S transition
- mdm2
A p53-regulatory protein that is reported as a SENP2 target for altered sumoylation in this work.
- p53
A stress-responsive regulatory protein whose level is modulated in the trophoblast experiments described here.
Aliases: p53 protein
- p53–mdm2 pathway
A regulatory pathway linking p53 and Mdm2 that controls p53 abundance and activity in the trophoblast setting.
Aliases: p53-Mdm2 pathway
- senp2
A SUMO-specific protease that removes SUMO from target proteins in the trophoblast context examined here.
Aliases: SUMO-specific protease 2
- sumoylation
A post-translational modification in which SUMO is attached to proteins such as Mdm2.
- trophoblast cells
Placenta-associated embryonic cells in which SENP2 expression is reported here.
Aliases: trophoblast
- trophoblast stem cell niches and lineages
The trophoblast stem-cell compartment and its differentiated descendant layers involved in placental development.
Aliases: trophoblast lineages, trophoblast stem cell niches
REFERENCES
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