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

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[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.

SUBMITTER: Fingerle-Rowson G

PROVIDER: S-EPMC170922 | biostudies-literature | 2003 Aug

REPOSITORIES: biostudies-literature

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

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

Proceedings of the National Academy of Sciences of the United States of America 20030723 16

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/ ...[more]

PMID: 12878730

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Project description:Autistic spectrum disorders are childhood neurodevelopmental disorders characterized by social and communicative impairment and repetitive and stereotypical behavior. Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes monocyte/macrophage-activation responses by increasing the expression of Toll-like receptors and inhibiting activation-induced apoptosis. On the basis of results of previous genetic linkage studies and reported altered innate immune response in autism spectrum disorder, we hypothesized that MIF could represent a candidate gene for autism spectrum disorder or its diagnostic components.Genetic association between autism spectrum disorder and MIF was investigated in 2 independent sets of families of probands with autism spectrum disorder, from the United States (527 participants from 152 families) and Holland (532 participants from 183 families). Probands and their siblings, when available, were evaluated with clinical instruments used for autism spectrum disorder diagnoses. Genotyping was performed for 2 polymorphisms in the promoter region of the MIF gene in both samples sequentially. In addition, MIF plasma analyses were conducted in a subset of Dutch patients from whom plasma was available.There were genetic associations between known functional polymorphisms in the promoter for MIF and autism spectrum disorder-related behaviors. Also, probands with autism spectrum disorder exhibited higher circulating MIF levels than did their unaffected siblings, and plasma MIF concentrations correlated with the severity of multiple autism spectrum disorder symptoms.These results identify MIF as a possible susceptibility gene for autism spectrum disorder. Additional research is warranted on the precise relationship between MIF and the behavioral components of autism spectrum disorder, the mechanism by which MIF contributes to autism spectrum disorder pathogenesis, and the clinical use of MIF genotyping.

Dataset Information

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

Publications

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

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