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 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.
Fingerle-Rowson
G
G
The Picower Institute for Medical Research, Manhasset, NY 11030, USA. g.fingerle-rowson@gmx.de
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
D000483:Alleles; D000818:Animals; D001564:Benzo(a)pyrene; D002273:Carcinogens; D004249:DNA Damage; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics / Q000473:pathology; D018014:Gene Transfer Techniques; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
D002273:Carcinogens; D008263:Macrophage Migration-Inhibitory Factors; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene