Macrophage migration inhibitory factor deficiency is associated with altered cell growth and reduced susceptibility to Ras-mediated transformation

Macrophage migration inhibitory factor (MIF) has been shown to functionally inactivate the p53 tumor suppressor and to inhibit p53-responsive gene expression and apoptosis. To better understand the role of MIF in cell growth and tumor biology, we evaluated MIF-null embryonic fibroblasts with respect to their immortalization and transformation properties. Although minor deviations in the growth characteristics of MIF-/- fibroblasts were observed under normal culture conditions, MIF-deficient cells were growth-impaired following the introduction of immortalizing oncogenes. The growth retardation by the immortalized MIF-/- cultures correlated with their reduced susceptibility to Ras-mediated transformation. Our results identify E2F as part of the restraining mechanism that is activated in response to oncogenic signaling and show that the biological consequences of E2F induction in MIF-/- fibroblasts vary depending on the p53 status, inducing predominantly G(1) arrest or apoptosis in p53-positive cells. This E2F activity is independent of Rb binding, but contingent on binding DNA. Resistance to oncogenic transformation by MIF-/- cells could be overcome by concomitant interference with p53- and E2F-responsive transcriptional control. Our results demonstrate that MIF plays a role in an E2F/p53 pathway that operates downstream of Rb regulation and implicate MIF as a mediator of normal and malignant cell growth.