ZAS3 promotes TNF alpha-induced apoptosis by blocking NF kappa B-activated expression of the anti-apoptotic genes TRAF1 and TRAF2

摘要

ZAS3 is a large zinc finger transcription repressor that binds the kappa B-motif via two signature domains of ZASN and ZASC. A loss-of-function study showed that lack of ZAS3 protein induced accelerated cell proliferation and tumorigenesis. Conversely, gain-of-function studies showed that ZAS3 repressed NF kappa B-activated transcription by competing with NF kappa B for the kappa B-motif. Based on these observations, we hypothesize that ZAS3 promotes apoptosis by interrupting anti-apoptotic activity of NF kappa B. Here, we present evidence that upon TNF alpha stimulation, ZAS3 inhibits NF kappa B-mediated cell survival and promotes caspase-mediated apoptosis. The inhibitory effect of ZAS3 on NF kappa B activity is mediated by neither direct association with NF kappa B nor disrupting nuclear localization of NF kappa B. Instead, ZAS3 repressed the expression of two key anti-apoptotic genes of NF kappa B, TRAF1 and TRAF2, thereby sensitizing cells to TNF alpha-induced cell death. Taken together, our data suggest that ZAS3 is a tumor suppressor gene and therefore serves as a novel therapeutic target for developing anti-cancer drugs. [BMB reports 2011; 44(4): 267-272]