A Splicing Variant of NME1 Negatively Regulates NF-κB Signaling and Inhibits Cancer Metastasis by Interacting with IKKβ
- A Splicing Variant of NME1 Negatively Regulates NF-κB Signaling and Inhibits Cancer Metastasis by Interacting with IKKβ
- 유동주; 박초롱; 이현복; 문미진; 강주희; 이철주; 오성현; 안규리; 성재현; 황종익
- Issue Date
- The Journal of biological chemistry
- VOL 289, NO 25, 17709-17720
- IKKβ functions as a principal upstream activator of the canonical NF-κB pathway by phosphorylating IκB, leading to its proteasomal degradation. Because IKKβ is considered a therapeutic target, understanding its regulation may facilitate the design of efficient regulators of this molecule. Here, we report a novel IKKβ-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 IKKβ. Exogenous expression of NME1L resulted in a potent decrease in TNFα-stimulated NF-κB activation, whereas knockdown of NME1/NME1L with shRNA enhanced activity of NF-κB. NME1L down-regulates IKKβ signaling by blocking IKKβ-mediated IκB 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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