RESUMEN
The mechanism of protein post-translational modifications in regulation of cell mitosis and genomic stability is always a hot issue in biological researches. The present review introduced the functional activity of de-SUMOylase SENP3 in sister chromatin dissociation at mitosis, and demonstrated a new molecular mechanism of cross-talk regulation between protein SUMOylation and phosphorylation in maintaining genomic stability.
RESUMEN
Objective • To explore the effect of de-SUMOylation of p53 by SENP3 on its transcriptional activity in lung cancer. Methods • Lung cancer cell lines A549 (p53 wild type) and H1299 (p53 null) were used. Wild type p53 as well as sumoless mutants K386R or E388A were introduced into the cells. Co-immunoprecipitation was performed to detect SUMOylation of p53 under resting status or oxidative stress. Immunofluorescence was applied to observe the localization of p53 WT and K386R or E388A. Dual luciferase reporter assay and quantitative real-time PCR of p21 were performed to monitor the transcriptional activity of p53 WT and K386R or E388A. Growth curve was analyzed to demonstrate the effect of p53 WT and K386R or E388A on cell proliferation. Results • SENP3 was able to mediate de-SUMOylation modification of p53 under oxidative stress. Similar to WT p53, K386R and E388A p53 kept nuclear localization. Further, SENP3 knockdown or oxidative stress did not induce translocation of p53 from nucleus to cytoplasm. However, compared to WT, the transcriptional activation of K386R and E388A p53 were inhibited. Moreover, SENP3 inhibited the activity of p53 in A549. K386R and E388A p53 attenuated the inhibitive activity on cell proliferation in H1299. Conclusion • SENP3-mediated de-SUMOylation of p53 is one of mechanisms of its inactivation as tumor suppressor in lung cancer.
RESUMEN
SUMOylation is recently found to function as a targeting signal for the degradation of substrates through the ubiquitin-proteasome system. RNF4 is the most studied human SUMO-targeted ubiquitin E3 ligase. However, the relationship between SUMO proteases, SENPs, and RNF4 remains obscure. There are limited examples of the SENP regulation of SUMO2/3-targeted proteolysis mediated by RNF4. The present study investigated the role of SENP3 in the global protein turnover related to SUMO2/3-targeted ubiquitination and focused in particular on the SENP3 regulation of the stability of Sp1. Our data demonstrated that SENP3 impaired the global ubiquitination profile and promoted the accumulation of many proteins. Sp1, a cancer-associated transcription factor, was among these proteins. SENP3 increased the level of Sp1 protein via antagonizing the SUMO2/3-targeted ubiquitination and the consequent proteasome-dependent degradation that was mediated by RNF4. De-conjugation of SUMO2/3 by SENP3 attenuated the interaction of Sp1 with RNF4. In gastric cancer cell lines and specimens derived from patients and nude mice, the level of Sp1 was generally increased in parallel to the level of SENP3. These results provided a new explanation for the enrichment of the Sp1 protein in various cancers, and revealed a regulation of SUMO2/3 conjugated proteins whose levels may be tightly controlled by SENP3 and RNF4.