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

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]

Gene expression of tumor necrosis factor receptor associated‐factor (TRAF)‐1 and TRAF‐2 in inflammatory bowel disease

“…It is suggested that the TRAF‐2‐binding BIR1 domain of cIAP2/MALT1 fusion protein is critical for activating NF‐κB and the domain can increase the expression of the NF‐κB target gene, including TRAF‐1 . ZAS3 can repress the TRAF‐1 and TRAF‐2 gene expression and then suppress the NF‐κB anti‐apoptotic process …”

“…21 ZAS3 can repress the TRAF-1 and TRAF-2 gene expression and then suppress the NF-kB anti-apoptotic process. 27 T cells play crucial roles in the development of IBD but the relationship between the activity of T cells and the TRAF family is not quite clear. Resent researches have shown that both TRAF-1 and TRAF-2 are required in the T cell response to 4-1BB signaling, and 4-1BB recruits TRAF-1 and TRAF-2 to mediate survival signaling in T cells.…”

Parkin induces apoptotic cell death in TNF-α-treated cervical cancer cells

“…TNF-α is a pro-inflammatory cytokine secreted by macrophages and TNF-α exerts a suppressive effect on tumors (16). However, tumors can become TNF-α resistant and eventually most malignant tumors become TNF-α resistant (17,18). For these reasons, many malignant tumors can escape from TNF-α-induced cell death (17).…”

Longitudinal genome-wide DNA methylation changes in response to kidney failure replacement therapy

“…Numerous genes have been shown to be closely involved in apoptotic and proliferative cellular processes, which is interesting given the established links between apoptosis, vascular calcification and CVD 10 – 12 , 29 , 30 . HIVEP3 31 , EID2 32 , ETS1 33 , MRFAP1 34 , ZNF224 35 , BCL11B 36 , 37 , SKI 38 , 39 , ZMIZ1 40 , GFI1 41 , HDAC4 42 , MAD1L1 43 , NCOR2 44 , 45 , ANKRD11 46 , BANP 47 , and ARID3A 48 , 49 all have functions related to apoptosis, cell survival or cell cycle progression. This highlights the importance of cell cycle activity, apoptosis, and cellular senescence in CKD.…”