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BMC Mol Biol. 2007 Jun 13;8:50.

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.

Author information

1
Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, ROC. qyhong68@hotmail.com <qyhong68@hotmail.com>

Abstract

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 phospho-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.

PMID:
17567906
PMCID:
PMC1904229
DOI:
10.1186/1471-2199-8-50
[Indexed for MEDLINE]
Free PMC Article
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