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, Pro13Gly1 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.Macrophage migration-inhibitory factor (MIF) is a widely expressed cytokine and upstream regulator of the immune response (23). Immunoneutralization and genetic knockout studies have established a central position for MIF in the host response to infection and tissue invasion (5, 9, 15). MIF's importance in human disease also has been revealed by the association of high-expression MIF alleles with clinical severity of different autoimmune disorders (18).An important role for MIF in tumorigenesis and in the contribution of inflammation to cancer development also has been proposed (7,20). Different tumor types express high levels of MIF, and clinical studies have shown that MIF production correlates with tumor aggressiveness and metastatic potential (1,22,27). Studies using genetically engineered MIFdeficient cells and mice show that MIF contributes to the development of the malignant phenotype by several mechanisms, including enhancement of cell cycle progression by sustained mitogen-activated protein kinase (MAPK) activation (28, 30), decreased proteasomal protein degradation (33) leading to altered expression of key cell cycle-regulatory proteins (15,21,35), and tumor promotion by neoangiogenesis (10, 48). Importantly, MIF also inhibits the proapoptotic and cell cycleregulatory function of the p53 tumor suppressor, thereby allowing for the accumulation of oncogenic mutations (20, 32). MIF's role in tumor progression additionally is supported by human genetic studies, and a recent report has described an association between high-expression MIF alleles and incidence of prostate cancer, which is a tumor type in which recurrent inflammation is considered to have an etiologic role (27).Information regarding MIF structure and function has emerged only in the last few year...
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