ZAS3 promotes TNFα-induced apoptosis by blocking NFκB-activated expression of the anti-apoptotic genes TRAF1 and TRAF2

ZAS3 is a large zinc finger transcription repressor that binds the κB-motif via two signature domains of ZASN and ZASC. A loss-of-function study showed that lack of ZAS3 protein in- duced accelerated cell proliferation and tumorigenesis. Con- versely, gain-of-function studies showed that ZAS3 repressed NFκB-activated transcription by competing with NFκB for the κB-motif. Based on these observations, we hypothesize that ZAS3 promotes apoptosis by interrupting anti-apoptotic activ- ity of NFκB. Here, we present evidence that upon TNFα stim- ulation, ZAS3 inhibits NFκB-mediated cell survival and pro- motes caspase-mediated apoptosis. The inhibitory effect of ZAS3 on NFκB activity is mediated by neither direct associa- tion with NFκB nor disrupting nuclear localization of NFκB. Instead, ZAS3 repressed the expression of two key anti-apop- totic genes of NFκB, TRAF1 and TRAF2, thereby sensitizing cells to TNFα-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)