The p53-Dependent Effects of Macrophage Migration Inhibitory Factor Revealed by Gene Targeting

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 a...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2003-08, Vol.100 (16), p.9354-9359
Main Authors: Fingerle-Rowson, G., Petrenko, O., Metz, C. N., Forsthuber, T. G., Mitchell, R., Huss, R., Moll, U., Müller, W., Bucala, R.
Format: Article
Language:English
Subjects:
Alleles
Animals
Apoptosis
Benzo(a)pyrene
Biological Sciences
Carcinogenesis
Carcinogens
Cell growth
Cellular biology
Cytokines
DNA Damage
Exons
Fibroblasts
Fibroblasts - metabolism
Fibrosarcoma - genetics
Fibrosarcoma - pathology
Gene Transfer Techniques
Genes
Genomics
Macrophage Migration-Inhibitory Factors - metabolism
Macrophage Migration-Inhibitory Factors - physiology
Macrophages
Medical genetics
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
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1533295100