期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 29, 期 7, 页码 1922-1932出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01907-08
关键词
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资金
- NIH [AI042310, AR049610, AR050498]
- German Research Council (DFG) [Fi 712/2-1, Be 1977/4-1]
- RWTH Aachen University START
- Koeln Fortune Program of the Medical Faculty of Cologne University
Macrophage migration-inhibitory factor (MIF) is an upstream regulator of innate immunity and a potential molecular link between inflammation and cancer. The unusual structural homology between MIF and certain tautomerases, which includes both a conserved substrate-binding pocket and a catalytic N-terminal proline (Pro1), has fueled speculation that an enzymatic reaction underlies MIF's biologic function. To address the functional role of the MIF tautomerase activity in vivo, we created a knock-in mouse in which the endogenous mif gene was replaced by one encoding a tautomerase-null, Pro1 -> Gly1 MIF protein (P1G-MIF). While P1G-MIF is completely inactive catalytically, it maintains significant, albeit reduced, binding to its cell surface receptor (CD74) and to the intracellular binding protein JAB1/CSN5. P1G-MIF knock-in mice (mif(P1G/P1G)) and cells derived from these mice show a phenotype in assays of growth control and tumor induction that is intermediate between those of the wild type (mif(+/+)) and complete MIF deficiency (mif(-/-)). These data provide genetic evidence that MIF's intrinsic tautomerase activity is dispensable for this cytokine's growth-regulatory properties and support a role for the N-terminal region in protein-protein interactions.
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