Macrophage migration inhibitory factor MIF interferes with the Rb-E2F pathway

Mol Cell. 2005 Jan 21;17(2):225-36. doi: 10.1016/j.molcel.2004.11.052.

Abstract

Macrophage migration inhibitory factor (MIF) is implicated in the regulation of inflammation and cell growth. We previously showed that MIF is a potent modulator of p53- and E2F-dependent pathways that are activated in response to oncogenic signaling. Here, we characterize the functional link between MIF and E2F transcription factors. Our results demonstrate that MIF-deficient cells exhibit E2F-dependent growth alterations and reduced susceptibility to oncogenic transformation. The basis for this transformation resistance is a perturbed function of the C-terminal Rb binding region of E2F4. However, inactivation of Rb or substitution of the E2F4 C-terminal domain by the E2F1 C-terminal region rescues the transformation defect. Importantly, the involvement of E2F factors in DNA replication rather than in regulation of transcription determines their oncogenic properties in the context of MIF deficiency. A proinflammatory molecule interfering with tumor suppression and DNA replication provides a compelling molecular link for the association of chronic inflammation and tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation
  • Cell Transformation, Neoplastic*
  • Cells, Cultured
  • DNA Replication
  • DNA-Binding Proteins / metabolism*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F4 Transcription Factor
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression Regulation
  • Genes, ras
  • Macrophage Migration-Inhibitory Factors / genetics
  • Macrophage Migration-Inhibitory Factors / metabolism*
  • Mice
  • Mice, Knockout
  • Neoplasms / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Retinoblastoma Protein / metabolism*
  • Signal Transduction / physiology*
  • Transcription Factors / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • ras Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F4 Transcription Factor
  • E2f1 protein, mouse
  • E2f4 protein, mouse
  • Macrophage Migration-Inhibitory Factors
  • Retinoblastoma Protein
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • ras Proteins