Abstract
Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the Emu-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 Emu-Myc B-cells 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 Emu-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 Myc-mediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Apoptosis / genetics
-
Apoptosis / physiology
-
B-Lymphocytes / cytology
-
B-Lymphocytes / metabolism
-
B-Lymphocytes / physiology
-
Cell Cycle Proteins / metabolism
-
DNA-Binding Proteins / metabolism
-
E2F Transcription Factors
-
Female
-
Gene Deletion
-
Gene Expression
-
Genes, myc / genetics
-
In Situ Nick-End Labeling
-
Lymphoma, B-Cell / genetics
-
Lymphoma, B-Cell / metabolism*
-
Macrophage Migration-Inhibitory Factors / deficiency*
-
Macrophage Migration-Inhibitory Factors / genetics
-
Macrophage Migration-Inhibitory Factors / physiology
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Transgenic
-
Proto-Oncogene Proteins c-myc / genetics
-
Proto-Oncogene Proteins c-myc / physiology*
-
Reverse Transcriptase Polymerase Chain Reaction
-
Transcription Factors / metabolism
-
Tumor Suppressor Protein p14ARF / genetics
-
Tumor Suppressor Protein p14ARF / metabolism
-
Tumor Suppressor Protein p53 / genetics
-
Tumor Suppressor Protein p53 / metabolism
Substances
-
Cell Cycle Proteins
-
DNA-Binding Proteins
-
E2F Transcription Factors
-
Macrophage Migration-Inhibitory Factors
-
Proto-Oncogene Proteins c-myc
-
Transcription Factors
-
Tumor Suppressor Protein p14ARF
-
Tumor Suppressor Protein p53