Article
- The EMBO Journal (2007) 26, 987 - 997
- doi:10.1038/sj.emboj.7601564
Published online: 8 February 2007
Subject Categories:
Impaired DNA damage checkpoint response in MIF-deficient mice
Alice Nemajerova1, Patricio Mena1, Gunter Fingerle-Rowson2, Ute M Moll1 and Oleksi Petrenko1
- Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY, USA
- University Hospital Cologne, Medical Clinic I, Hematology and Oncology, Cologne, Germany
Correspondence to:
Oleksi Petrenko, Department of Pathology, State University of New York at Stony Brook, BST L9, Stony Brook, NY 11794, USA. Tel.: +1 631 444 3520; Fax: +1 631 444 3424; E-mail: apetrenko@notes.cc.sunysb.edu
Received 18 May 2006; Accepted 20 December 2006
Abstract
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.
Keywords:
- DNA damage,
- E2F1,
- p53,
- replication,
- SCF complex
