Regulation Of REGγ On The GSK3β Activity And Degradation

Glycose synthase kinase 3 (GSK3), originally named for its role in the glycose synthesis, is a mutifunctional kinase that regulates many important biological processes such as WNT-mediated functions, insulin sensitivity, self-renewal of the hematopo ietic stem cell, cell cycle, apoptosis, as well as tumorigenesis. In mammals, there exist two isoforms of GSK3, called GSK3α(51kD) and GSK3β(47kD) which are encoded by two different genes respectively. REGγ, a member of the 11s proteasome activators, has been shown to bind and activate the 20s proteasome and trigger Ubi-dependent degradation of important regulatory proteins. In this paper, we investigated the biological significance of the interaction between REGγand GSK3β.We found that REGγbound to GSK3βand triggered degradation of the GSK3βprotein. Overexpression of REGγreduced GSK3βprotein level, while depletion of REGγby exploying a specific targeting shRNA or gene knockout approaches increased the GSK3βprotein level. Interestingly, REGγrelocalized GSK3βfrom the cytoplasm to the nucleus. We also observed that depletion of REGγin cells promoted GSK3βexpression, which in turn resulted in an increasing phosphorylation of p53 on the Ser315 residue and the decreasingβ-catenin protein level Moreover, we showed that REGγregulated p53 transactivity and degradation of p53 via the interaction with GSK3β, and as a result overexpression of REGγattenuated cell apoptosis.Taken together, we found that REGγdegradates GSK3βleading to the dephosphorylation of GSK3βtaget proteins. This new regulatory mechanism of GSK3βdegradation may provide significant platform, where we can explore the biological functions of GSK3βand its target proteins.