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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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ZAS3 promotes TNFα-induced apoptosis by blocking NFκB-activated expression of the anti-apoptotic genes TRAF1 and TRAF2

  • Shin, Dong-Hyeon (The Graduate School of East-West Medical Science, Kyung Hee University) ;
  • Park, Kye-Won (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Wu, Lai-Chu (Department of Molecular and Cellular Biochemistry, College of Medicine and Public Health, The Ohio State University) ;
  • Hong, Joung-Woo (The Graduate School of East-West Medical Science, Kyung Hee University)
  • Received : 2011.01.17
  • Accepted : 2011.02.01
  • Published : 2011.04.30
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Abstract

ZAS3 is a large zinc finger transcription repressor that binds the ${\kappa}B$-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 $NF{\kappa}B$-activated transcription by competing with $NF{\kappa}B$ for the ${\kappa}B$-motif. Based on these observations, we hypothesize that ZAS3 promotes apoptosis by interrupting anti-apoptotic activity of $NF{\kappa}B$. Here, we present evidence that upon $TNF{\alpha}$ stimulation, ZAS3 inhibits $NF{\kappa}B$-mediated cell survival and promotes caspase-mediated apoptosis. The inhibitory effect of ZAS3 on $NF{\kappa}B$ activity is mediated by neither direct association with $NF{\kappa}B$ nor disrupting nuclear localization of $NF{\kappa}B$. Instead, ZAS3 repressed the expression of two key anti-apoptotic genes of $NF{\kappa}B$, TRAF1 and TRAF2, thereby sensitizing cells to $TNF{\alpha}$-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.

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References

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