ZAS3 promotes TNFα-induced apoptosis by blocking NFκB-activated expression of the anti-apoptotic genes TRAF1 and TRAF2
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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 induced accelerated cell proliferation and tumorigenesis. Conversely,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 activity of NFκB. Here, we present evidence that upon TNFα stimulation,ZAS3 inhibits NFκB-mediated cell survival and promotes caspase-mediated apoptosis. The inhibitory effect of ZAS3 on NFκB activity is mediated by neither direct association with NFκB nor disrupting nuclear localization of NFκB. Instead, ZAS3 repressed the expression of two key anti-apoptotic 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]
Abstract
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 induced accelerated cell proliferation and tumorigenesis. Conversely,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 activity of NFκB. Here, we present evidence that upon TNFα stimulation,ZAS3 inhibits NFκB-mediated cell survival and promotes caspase-mediated apoptosis. The inhibitory effect of ZAS3 on NFκB activity is mediated by neither direct association with NFκB nor disrupting nuclear localization of NFκB. Instead, ZAS3 repressed the expression of two key anti-apoptotic 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]
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