Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1

• DOI: 10.1038/35041591
• Publication Date: 2002-07-26T08:33:27Z
• Authors: Robert Kleemann; Angelika Hausser; Georg Geiger; Ralf Mischke; Anke Burger-Kenti...; Oliver Flieger; Franz-Josef Johannes; Thierry Roger; Thierry Calandra; Aphrodite Kapurniotu; Matthias Grell; Doris Finkelmeier; Herwig Brunner; Jürgen Bernhagen
• Keywords: Mitogen-Activated Protein Kinase Kinases; 0303 health sciences; COP9 Signalosome Complex; MAP Kinase Kinase 4; Cell Cycle; Intracellular Signaling Peptides and Proteins; JNK Mitogen-Activated Protein Kinases; NF-kappa B; Cell Cycle Proteins; Precipitin Tests; Cell Line; DNA-Binding Proteins; 03 medical and health sciences; Gene Expression Regulation; Humans; Luciferases; Macrophage Migration-Inhibitory Factors; Microtubule-Associated Proteins; Cyclin-Dependent Kinase Inhibitor p27; HeLa Cells; Peptide Hydrolases; Protein Binding

Cytokines are multifunctional mediators that classically modulate immune activity by receptor-mediated pathways. Macrophage migration inhibitory factor (MIF) is a cytokine that has a critical role in several inflammatory conditions but that also has endocrine and enzymatic functions. The molecular targets of MIF action have so far remained unclear. Here we show that MIF specifically interacts with an intracellular protein, Jab1, which is a coactivator of AP-1 transcription that also promotes degradation of the cyclin-dependent kinase inhibitor p27Kip1 (ref. 10). MIF colocalizes with Jab1 in the cytosol, and both endogenous and exogenously added MIF following endocytosis bind Jab1. MIF inhibits Jab1- and stimulus-enhanced AP-1 activity, but does not interfere with the induction of the transcription factor NFkappaB. Jab1 activates c-Jun amino-terminal kinase (JNK) activity and enhances endogenous phospho-c-Jun levels, and MIF inhibits these effects. MIF also antagonizes Jab1-dependent cell-cycle regulation by increasing p27Kip1 expression through stabilization of p27Kip1 protein. Consequently, Jab1-mediated rescue of fibroblasts from growth arrest is blocked by MIF. Amino acids 50-65 and Cys 60 of MIF are important for Jab1 binding and modulation. We conclude that MIF may act broadly to negatively regulate Jab1-controlled pathways and that the MIF-Jab1 interaction may provide a molecular basis for key activities of MIF.