SUMO Modification Of REGγ And Its Functions

We are constantly looking for the methods for cancer prevention and therapy when the cancer morbidities in the world are increasing. In the past decades, cancer research has made encouraging progress; but prevention and treatment of cancers have not been perfected. Recent years, proteasome inhibitors have been shown to be an exciting and effective treatment for cancers. Proteasome is a complex which can catalyze proteolysis. REGγis a 11s proteasome activator. The biological roles of REGγare yet to be explored. We previously demonstrated that REGγ/proteasome could degrade SRC-3 which is an oncogene frequently amplified and overexpressed in breast cancers. It's suggested that REGγcan regulate the process of tumor development. Moreover, we also found p21 is another target protein of REGγ/proteasome, which revealed REGγalso had a role in the regulation of the cell cycle through its ability to influence the level of a cell-cycle regulator(s). Thus further studies on REGγ/proteasome may lead to novel therapeutics for cancer. Posttranslational modifications are modifications that cells used to control the function of proteins. SUMO modification is one kind of posttranslational modification. SUMO is a small poly-peptide which is structurally related to ubiquitin. Unlike the situation with ubiquitination, SUMO modification does not appear to target proteins for proteasome-mediated degradation and it is a reversible process. A number of studies show that SUMO modification can alter the stability of the target protein and will also affect protein subcellular distribution, protein function, protein-protein interaction.In our study we found that REGγcan be SUMOylated in vitro and in vivo. So we analyzed the amino acid sequence of REGγusing different professional software and predicted several sites as potential SUMOylation sites. The SUMO-E3 protein inhibitor of activated STAT (PIAS)1 physically associates with REGγand promotes SUMOylation of REGγ. SUMO modification of REGγwas found to occur at multiple sites, including K6, K14, and K12. Mutation analysis indicated that these SUMO sites simultaneously contributed to the SUMOylation status of REGγin cells. SUMO modification of REGγwas revealed to mediate subcellular distribution of REGγand also increased stability of this proteasome activator. SUMOylation-deficient REGγdisplayed attenuated ability to degrade p21Waf//Cip1 due to reduced affinity of the REGγSUMOylation-defective mutant for p21. Taken together, we report a previously unrecognized mechanism regulating the activity of the proteasome activator REGγ. This regulatory mechanism may enable REGγto function as a more potent factor in protein degradation with a broader substrate spectrum.