Macrophage migration inhibitory factor interacts with thioredoxin-interacting protein and induces NF-κB activity

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Macrophage migration inhibitory factor interacts with thioredoxin-interacting protein and induces NF-κB activity
Mi Jeong Kim; Won Sam Kim; Dong Oh Kim; Jae-Eun Byun; H Huy; Soo Yun Lee; Hae Young Song; Young-Jun ParkTae-Don KimSuk Ran Yoon; E J Choi; H Ha; Haiyoung Jung; In Pyo Choi
Bibliographic Citation
Cellular Signalling, vol. 34, pp. 110-120
Publication Year
The nuclear factor kappa B (NF-κB) pathway is pivotal in controlling survival and apoptosis of cancer cells. Macrophage migration inhibitory factor (MIF), a cytokine that regulates the immune response and tumorigenesis under inflammatory conditions, is upregulated in various tumors. However, the intracellular functions of MIF are unclear. In this study, we found that MIF directly interacted with thioredoxin-interacting protein (TXNIP), a tumor suppressor and known inhibitor of NF-κB activity, and MIF significantly induced NF-κB activation. MIF competed with TXNIP for NF-κB activation, and the intracellular MIF induced NF-κB target genes, including c-IAP2, Bcl-xL, ICAM-1, MMP2 and uPA, by inhibiting the interactions between TXNIP and HDACs or p65. Furthermore, we identified the interaction motifs between MIF and TXNIP via site-directed mutagenesis of their cysteine (Cys) residues. Cys57 and Cys81 of MIF and Cys36 and Cys120 of TXNIP were responsible for the interaction. MIF reversed the TXNIP-induced suppression of cell proliferation and migration. Overall, we suggest that MIF induces NF-κB activity by counter acting the inhibitory effect of TXNIP on the NF-κB pathway via direct interaction with TXNIP. These findings reveal a novel intracellular function of MIF in the progression of cancer.
Appears in Collections:
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
Division of Research on National Challenges > Environmental diseases research center > 1. Journal Articles
Aging Convergence Research Center > 1. Journal Articles
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