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Characterization of Functional Domains in NME1L Regulation of NF-κB Signaling

  • You, Dong-Joo (Graduate School of Medicine, Korea University) ;
  • Park, Cho Rong (Graduate School of Medicine, Korea University) ;
  • Mander, Sunam (Graduate School of Medicine, Korea University) ;
  • Ahn, Curie (Transplantation Research Institute, Cancer Research Institute, Seoul National University) ;
  • Seong, Jae Young (Graduate School of Medicine, Korea University) ;
  • Hwang, Jong-Ik (Graduate School of Medicine, Korea University)
  • Received : 2015.11.25
  • Accepted : 2016.02.29
  • Published : 2016.05.31

Abstract

NME1 is a well-known metastasis suppressor which has been reported to be downregulated in some highly aggressive cancer cells. Although most studies have focused on NME1, the NME1 gene also encodes the protein (NME1L) containing N-terminal 25 extra amino acids by alternative splicing. According to previous studies, NME1L has potent anti-metastatic activity, in comparison with NME1, by interacting with $IKK{\beta}$ and regulating its activity. In the present study, we tried to define the role of the N-terminal 25 amino acids of NME1L in $NF-{\kappa}B$ activation signaling. Unfortunately, the sequence itself did not interact with $IKK{\beta}$, suggesting that it may be not enough to constitute the functional structure. Further construction of NME1L fragments and biochemical analysis revealed that N-terminal 84 residues constitute minimal structure for homodimerization, $IKK{\beta}$ interaction and regulation of $NF-{\kappa}B$ signaling. The inhibitory effect of the fragment on cancer cell migration and $NF-{\kappa}B$-stimulated gene expression was equivalent to that of whole NME1L. The data suggest that the N-terminal 84 residues may be a core region for the anti-metastatic activity of NME1L. Based on this result, further structural analysis of the binding between NME1L and $IKK{\beta}$ may help in understanding the anti-metastatic activity of NME1L and provide direction to NME1L and $IKK{\beta}$-related anti-cancer drug design.

Keywords

anti-metastasis;dimerization;$IKK{\beta}$;$NF-{\kappa}B$;NME1L

Acknowledgement

Supported by : Korea Research Foundation

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