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Fingerle-Rowson, G, Petrenko, O, Metz, CN, Forsthuber, TG, Mitchell, R, Huss, R, Moll, U, Müller, W and Bucala, R (2003) The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc. Natl. Acad. Sci. U.S.A. 100:9354-9
Macrophage migration inhibitory factor (MIF) is a mediator of host immunity and functions as a high, upstream activator of cells within the innate and the adaptive immunological systems. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. To better understand MIF's activity in growth control, we generated and characterized a strain of MIF-knockout (MIF-KO) mice in the inbred, C57BL/6 background. Embryonic fibroblasts from MIF-KO mice exhibit p53-dependent growth alterations, increased p53 transcriptional activity, and resistance to ras-mediated transformation. Concurrent deletion of the p53 gene in vivo reversed the observed phenotype of cells deficient in MIF. In vivo studies showed that fibrosarcomas induced by the carcinogen benzo[alpha]pyrene are smaller in size and have a lower mitotic index in MIF-KO mice relative to their WT counterparts. The data provide direct genetic evidence for a functional link between MIF and the p53 tumor suppressor and indicate an important and previously unappreciated role for MIF in carcinogenesis.
Alleles; Animals; Benzo(a)pyrene; Carcinogens; DNA Damage; Exons; Fibroblasts/metabolism; Fibrosarcoma/genetics; Fibrosarcoma/pathology; Gene Transfer Techniques; Macrophage Migration-Inhibitory Factors/metabolism; Macrophage Migration-Inhibitory Factors/physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Models, Genetic; Mutation; Phenotype; Retroviridae/genetics; Time Factors; Transcription, Genetic; Transcriptional Activation; Tumor Suppressor Protein p53/metabolism; Tumor Suppressor Protein p53/physiology
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