2932

GSK3B

-;glycogen synthase kinase 3 beta;GSK3B;glycogen synthase kinase 3 beta

GSK-3 beta|GSK3beta isoform|glycogen synthase kinase-3 beta|serine/threonine-protein kinase GSK3B

3q13.3

protein-coding

Glycogen synthase kinase 3beta (GSK3beta) reportedly has opposing roles, repressing Wnt/beta-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-kappaB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3beta in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3beta expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of beta-catenin oncoprotein in the tumor cells. Inhibition of GSK3beta activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3beta activity by chemical inhibitors and its expression by RNA interference targeting GSK3beta induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3beta in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer.

Apoptosis is critical for embryonic development, tissue homeostasis, and tumorigenesis and is determined largely by the Bcl-2 family of antiapoptotic and prosurvival regulators. Here, we report that glycogen synthase kinase 3 (GSK-3) was required for Mcl-1 degradation, and we identified a novel mechanism for proteasome-mediated Mcl-1 turnover in which GSK-3beta associates with and phosphorylates Mcl-1 at one consensus motif ((155)STDG(159)SLPS(163)T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 with the E3 ligase beta-TrCP, and beta-TrCP then facilitates the ubiquitination and degradation of phosphorylated Mcl-1. A variant of Mcl-1 (Mcl-1-3A), which abolishes the phosphorylations by GSK-3beta and then cannot be ubiquitinated by beta-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3beta and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by beta-TrCP is an essential mechanism for GSK-3beta-induced apoptosis and contributes to GSK-3beta-mediated tumor suppression and chemosensitization.