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| Subject Categories: Cell Cycle | Molecular Biology of Disease |
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| The EMBO Journal
(2007) 26, 987–997, doi:10.1038/sj.emboj.7601564 Published online 8 February 2007 |
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| Impaired DNA damage checkpoint response in MIF-deficient mice |
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| Alice Nemajerova1, Patricio Mena1, Gunter Fingerle-Rowson2, Ute M Moll1 and Oleksi Petrenko1 |
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1 Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY, USA 2 University Hospital Cologne, Medical Clinic I, Hematology and Oncology, Cologne, Germany To whom correspondence should be addressed 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; Published online 8 February 2007. |
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| Abstract |
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| 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. |
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| Keywords: DNA damage, E2F1, p53, replication, SCF complex |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHImpaired DNA damage checkpoint response in MIF-deficient mice The EMBO Journal Article Oncogene Original Article Oncogene Original Article |
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