SUMO-specific protease 2 in Mdm2-mediated regulation of p53

Abstract

Genetic analysis in mice has revealed a key genetic pathway, SUMO-specific protease 2 (SENP2)-Mdm2-p53, essential for trophoblast development. Targeted disruption of SENP2 impairs the G-S transition required for mitotic and endoreduplication cell cycles during the expansion of trophoblast stem cells and their differentiation into polyploidy cells, respectively. The disruption disturbed the subcellular distribution and SUMO modification of Mdm2, leading to interference with p53 degradation. Here, we further explore the mechanism underlying SENP2-mediated regulation of Mdm2 in p53-induced cellular stress. We identify a specific isoform of SENP2 necessary and sufficient to negatively regulate the p53-dependent transcription and its related stress responses. This isoform-specific effect is attributed to the differential compartmentalization of SENP2. SUMO conjugation of Mdm2 induces its co-localization and association with SENP2 in promyelocytic leukemia bodies. Biochemical studies show that SENP2 catalyzes the desumoylation process of Mdm2. SENP2-dependent regulation of Mdm2 is sensitive to its p53-binding activity. Our findings led us to propose a mechanism underlying the SENP2-mediated regulation of Mdm2 that is critical for genome integrity in p53-dependent stress responses. Cell Death and Differentiation (2011) 18, 1005-1015; doi:10.1038/cdd.2010.168; published online 24 December 2010Small ubiquitin-related modifier (SUMO, also known as sentrin) is a member of the ubiquitin-like modifier family. 1 This covalent conjugation process is reversible and highly evolutionarily conserved among species. 2 SUMO functions in a manner similar to ubiquitin, where it is bound to target proteins as part of a post-translational modification system. However, unlike ubiquitination with a well-established role in targeting protein degradation, SUMO modification is involved in a variety of cellular processes, including protein trafficking, transcriptional regulation, cell survival and death, and protein stability. 3 Many sumoylated proteins have been shown to preferentially accumulate in specific complexes such as the nuclear pore and promyelocytic leukemia (PML) bodies. 4,5 Similar to ubiquitination, sumoylation requires processing, conjugation and transfer. The transfer process, which covalently conjugates SUMO polypeptides to their targets, is catalyzed by E3 ligases. 6 The reverse desumoylation process is mediated by SUMO-specific proteases (SENPs). Although SENPs have been linked to catalyze SUMO modification in various physiological systems, their roles in mammalian development and pathogenesis remain largely elusive.We previously demonstrated that SENP2 is essential for modulating the p53/Mdm2 circuit in trophoblast development. 7 Targeted disruption of SENP2 in mice impaired the G-S transition required for mitotic and endoreduplication cell cycles during expansion of trophoblast stem (TS) cells and their differentiation into polyploid cells, respectively. 7 The SENP2 ablation apparently disturbed the subcellular distributi...

Integrative Genomics Analysis Identifies Candidate Drivers at 3q26-29 Amplicon in Squamous Cell Carcinoma of the Lung

“…MDM2-p53 is most well-studied SUMOmodified proteins. SENP2 promotes the deSUMOylation of Mdm2, contributing to the p53-dependent regulations (43). Interestingly, the tumour suppressor p53 has been shown to be modified at its C-terminus with ubiquitin, SUMO and NEDD8, although the consequence undergoing these post-translational modifications may differ (44).…”

De-SUMOylation Enzyme of Sentrin/SUMO-Specific Protease 2 Regulates Disturbed Flow–Induced SUMOylation of ERK5 and p53 that Leads to Endothelial Dysfunction and Atherosclerosis

“…Sentrin/SUMO-specific protease 2 (SENP2) is a de-SUMOylation enzyme that is important for both processing new SUMO proteins for conjugation as well as deconjugating SUMO from SUMOylated proteins 7–9 . Although six isoforms of SENPs exist in humans (SENP1–3 and 5–7), SENP2 specifically regulates p53 through Mdm2 de-SUMOylation, leading to apoptosis of cells 10, 11 .…”

Therapeutic potential of mitotic interaction between the nucleoporin Tpr and aurora kinase A

“…44, 45 We could not rule out the possibility that other pathways might also interact with Tpr in polyploidy formation. Further studies are necessary to clarify any other molecular events that are critical for Tpr function in cell cycle progression.…”