TI - Zfra affects TNF -mediated cell death by interacting with death domain protein TRADD and negatively regulates the activation of NF-kappaB , JNK1 , p53 and WOX1 during stress response . AB - Background Zfra is a 31-amino-acid zinc finger-like protein , which is known to regulate cell death by tumor necrosis factor ( TNF ) and overexpressed TNF receptor - or Fas-associated death domain proteins ( TRADD and FADD ) . In addition , Zfra undergoes self-association and interacts with c-Jun N-terminal kinase 1 ( JNK1 ) in response to stress stimuli . To further delineate the functional properties of Zfra , here we investigated Zfra regulation of the activation of p53 , WOX1 ( WWOX or FOR ) , NF-kappaB and JNK1 under apoptotic stress . Results Transiently overexpressed Zfra caused growth suppression and apoptotic death of many but not all types of cells . Zfra either enhanced or blocked cell death caused by TRADD , FADD or receptor-interacting protein ( RIP ) in a dose-related manner . This modulation is related with Zfra binding with TRADD , NF-kappaB , JNK1 and WOX1 , as determined by GST pull-down analysis , co-immunoprecipitation and mapping by yeast two hybrid analysis . Functionally , transiently overexpressed Zfra sequestered NF-kappaB ( p65 ) , WOX1 , p53 and PHOSphorylated ERK ( extracellular signal-activated kinase ) in the cytoplasm , and TNF or UV light could not effectively induce nuclear translocation of these proteins . Zfra counteracted the apoptotic functions of Tyr33 -phosphorylaTED WOX1 and Ser46 -PHOSphorylated p53 . Alteration of Ser8 to Gly abolished the apoptotic function of Zfra and its regulation of WOX1 and p53 . Conclusion In response to TNF , Zfra is upregulated and modulates TNF -mediated cell death via interacting with TRADD , FADD and RIP (death-inducing signaling complex) at the receptor level , and downstream effectors NF-kappaB , p53 , WOX1 and JNK1 .