The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting

G. Fingerle-Rowson, O. Petrenko, C. N. Metz, T. G. Forsthuber, R. Mitchell, R. Huss, U. Moll, W. Müller, R. Bucala

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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[α]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.
    Original languageEnglish
    Pages (from-to)9354-9359
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume100
    Issue number16
    DOIs
    Publication statusPublished - 5 Aug 2003

    Keywords

    • Carcinogenesis
    • Cytokines
    • P21
    • Transformation

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