Nature (London), 2000-11, Vol.408 (6809), p.211-216
2000
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1
- Ist Teil von
- Nature (London), 2000-11, Vol.408 (6809), p.211-216
- Ort / Verlag
- London: Nature Publishing
- Erscheinungsjahr
- 2000
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 p27 Kip1 (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 NFκB. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1038/35041591Titel-ID: cdi_proquest_miscellaneous_743347903
- Format
- –
- Schlagworte
- Analysis of the immune response. Humoral and cellular immunity, Biological and medical sciences, Cell cycle, Cell Cycle - physiology, Cell Cycle Proteins, Cell Line, Cells, COP9 Signalosome Complex, Cyclin-Dependent Kinase Inhibitor p27, Cytokines, DNA-Binding Proteins - physiology, Fundamental and applied biological sciences. Psychology, Fundamental immunology, Gene Expression Regulation, Genetic aspects, HeLa Cells, Humans, Immunobiology, Intracellular Signaling Peptides and Proteins, Jab1 protein, JNK Mitogen-Activated Protein Kinases, Kip1 protein, Luciferases - genetics, Lymphokines, interleukins ( function, expression), macrophage migration inhibitory factor, Macrophage Migration-Inhibitory Factors - physiology, MAP Kinase Kinase 4, Microtubule-Associated Proteins - metabolism, Mitogen-Activated Protein Kinase Kinases - metabolism, Molecules, NF-kappa B - metabolism, p27 protein, Peptide Hydrolases, Physiological aspects, Precipitin Tests, Protein Binding, Proteins, Proto-Oncogene Proteins c-jun - metabolism, Recombinant Fusion Proteins - genetics, Recombinant Fusion Proteins - metabolism, Regulatory factors and their cellular receptors, Transcription Factor AP-1 - antagonists & inhibitors, Transcription Factor AP-1 - physiology, Transcription factors, Transcription Factors - physiology, Tumor Suppressor Proteins