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

Fingerle‐Rowson, Günter; Petrenko, Oleksi; Metz, Christine N.; Forsthuber, Thomas G.; Mitchell, Robert A.; Huss, Ralf; Moll, Ute M.; Müller, Werner; Bucala, Richard

doi:10.1073/pnas.1533295100

Cited by 265 publications

(297 citation statements)

References 70 publications

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“…17,18,23 The data presented here implicate E2Fs in mediating this MIF-p53 connection. As we recently showed, loss of MIF augments Rb-mediated repression of E2F responsive genes and reduces the capacity for E2Fs to activate DNA replication, thereby impairing proliferation.…”

Section: Discussionmentioning

confidence: 53%

“…17 We previously showed that primary fibroblasts derived from MIF-deficient mice exhibit E2F-and p53-dependent growth defects and reduced susceptibility to oncogenic transformation. [23][24][25] Concurrent deletion of the p53 gene reversed the observed phenotype of cells deficient in MIF, providing the first genetic evidence for a functional link between MIF and the p53 tumor suppressor. 23 Here, we provide direct evidence for the tumor-promoting role of MIF in vivo.…”

Section: Introductionmentioning

confidence: 82%

“…[23][24][25] Concurrent deletion of the p53 gene reversed the observed phenotype of cells deficient in MIF, providing the first genetic evidence for a functional link between MIF and the p53 tumor suppressor. 23 Here, we provide direct evidence for the tumor-promoting role of MIF in vivo. Using the Em-Myc lymphoma mouse model, we demonstrate that loss of MIF delays the onset of B-cell lymphoma development.…”

Section: Introductionmentioning

confidence: 82%

“…23 MIF þ /À p53 þ /À double heterozygous mice were derived by crossing between the MIF À/À and Trp53 tm1Tyj animals (Jackson Laboratory), both on the 129S1/ SvImJ background (referred to as 129Sv). MIF þ / þ p53 À/À (referred to as p53 À/À ) and MIF À/À p53 À/À (DKO) mice were derived from crosses between the double heterozygous animals.…”

Section: Mice and Tissue Culturementioning

confidence: 99%

“…[20][21][22] Several studies have indicated that activation of cell proliferation by MIF is due to a functional inactivation of the p53 tumor suppressor. 17,18,23 Thus, MIF overexpression extends the lifespan of primary cells in vitro, inhibits Myc-induced p53-dependent apoptosis, and protects macrophages from NO-induced apoptosis. 17 Conversely, when MIF is lost, cell survival and functions are compromised in a p53-dependent manner.…”

Section: Introductionmentioning

confidence: 98%

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MIF loss impairs Myc-induced lymphomagenesis

et al. 2005

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Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the El-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null El-Myc Bcells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type El-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Mycmediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.

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Section: Discussionmentioning

confidence: 53%