| First Author | Nemajerova A | Year | 2007 |
| Journal | EMBO J | Volume | 26 |
| Issue | 4 | Pages | 987-97 |
| PubMed ID | 17290223 | Mgi Jnum | J:120099 |
| Mgi Id | MGI:3703855 | Doi | 10.1038/sj.emboj.7601564 |
| Citation | Nemajerova A, et al. (2007) Impaired DNA damage checkpoint response in MIF-deficient mice. EMBO J 26(4):987-97 |
| abstractText | 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. |
