Recent studies demonstrated that proinflammatory migration inhibitory factor(MIF) blocks p53‐dependent apoptosis and interferes with the tumor suppressor activity of p53. To explore the mechanism underlying this MIF‐p53 relationship, we studied spontaneous tumorigenesis in genetically matched p53−/− and MIF−/−p53−/− mice. We show that the loss of MIF expression aggravates the tumor‐prone phenotype of p53−/− mice and predisposes them to a broader tumor spectrum, including B‐cell lymphomas and carcinomas. Impaired DNA damage response is at the root of tumor predisposition of MIF−/−p53−/− mice. We provide evidence that MIF plays a role in regulating the activity of Cul1‐containing SCF ubiquitin ligases. The loss of MIF expression uncouples Chk1/Chk2‐responsive DNA damage checkpoints from SCF‐dependent degradation of key cell‐cycle regulators such as Cdc25A, E2F1 and DP1, creating conditions for the genetic instability of cells. These MIF effects depend on its association with the Jab1/CSN5 subunit of the COP9/CSN signalosome. Given that CSN plays a central role in the assembly of SCF complexes in vivo, regulation of Jab1/CSN5 by MIF is required to sustain optimal composition and function of the SCF complex.