Impaired DNA damage checkpoint response in MIF-deficient mice.
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.
Nemajerova
Alice
A
Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY 11794, USA, and University Hospital Cologne, Medical Clinic I, Hematology and Oncology, Germany.
Mena
Patricio
P
Fingerle-Rowson
Gunter
G
Moll
Ute M
UM
Petrenko
Oleksi
O
D000818:Animals; D000075686:COP9 Signalosome Complex; D002453:Cell Cycle / Q000235:genetics*; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D042822:Genomic Instability / Q000235:genetics; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; D016159:Tumor Suppressor Protein p53; D044843:SKP Cullin F-Box Protein Ligases; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse