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A Splicing Variant of NME1 Negatively Regulates NF-kappa B Signaling and Inhibits Cancer Metastasis by Interacting with IKK beta

Authors
You, Dong-JooPark, Cho RongLee, Hyun BokMoon, Mi JinKang, Ju-HeeLee, CheoljuOh, Seong-HyunAhn, CurieSeong, Jae YoungHwang, Jong-Ik
Issue Date
20-6월-2014
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords
NF-kB; IKKb; metastasis
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v.289, no.25, pp.17709 - 17720
Indexed
SCIE
SCOPUS
Journal Title
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume
289
Number
25
Start Page
17709
End Page
17720
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/98211
DOI
10.1074/jbc.M114.553552
ISSN
0021-9258
Abstract
IKK beta functions as a principal upstream activator of the canonical NF-kappa B pathway by phosphorylating I kappa B, leading to its proteasomal degradation. Because IKK beta is considered a therapeutic target, understanding its regulation may facilitate the design of efficient regulators of this molecule. Here, we report a novel IKK beta-interacting molecule, NME1L, a splicing variant of the NME1 protein. NME1 has attracted attention in cancer research because of its antimetastatic activity and reduced expression in multiple aggressive types of cancer. However, the effect was just moderate but not dramatic in anti-cancer activities. We found that only NME1L interacts with IKK beta. Exogenous expression of NME1L resulted in a potent decrease in TNF alpha-stimulated NF-kappa B activation, whereas knockdown of NME1/NME1L with shRNA enhanced activity of NF-kappa B. NME1L down-regulates IKK beta signaling by blocking IKK beta-mediated I kappa B degradation. When NME1L was introduced into highly metastatic HT1080 cells, the mobility was efficiently inhibited. Furthermore, in a metastasis assay, NME1L-expressing cells did not colonize the lung. Based on these results, NME1L is a potent antimetastatic protein and may be a useful weapon in the fight against cancers.
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