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Molecular and Cellular Biology, April 2009, p. 1922-1932, Vol. 29, No. 7
0270-7306/09/$08.00+0 doi:10.1128/MCB.01907-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
A Tautomerase-Null Macrophage Migration-Inhibitory Factor (MIF) Gene Knock-In Mouse Model Reveals That Protein Interactions and Not Enzymatic Activity Mediate MIF-Dependent Growth Regulation
Günter Fingerle-Rowson,1
Dayananda Rao Kaleswarapu,1
Corinna Schlander,2
Nazanin Kabgani,1
Tania Brocks,1
Nina Reinart,1
Raymonde Busch,3
Anke Schütz,4
Hongqi Lue,4
Xin Du,5
Aihua Liu,5,6
Huabao Xiong,7
Yibang Chen,7
Alice Nemajerova,8
Michael Hallek,1
Jürgen Bernhagen,4
Lin Leng,5 and
Richard Bucala5*
Clinic I for Internal Medicine, Hematology and Oncology, University Hospital Cologne, Cologne, Germany,1 Medical Clinic III, Klinikum Grosshadern, Ludwig Maximilians University, Munich, Germany,2 Institute for Medical Statistics and Epidemiology of Technical University, Munich, Germany,3 Department of Biochemistry and Molecular Cell Biology, Institute of Biochemistry, RWTH, Aachen University, Aachen, Germany,4 Department of Medicine, Yale University School of Medicine, New Haven, Connecticut,5 Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming 650031, Yunnan, China,6 Department of Pharmacology, Immunobiology Center, Mt. Sinai School of Medicine, New York, New York,7 Department of Pathology, State University of New York at Stony Brook, Stony Brook, New York8
Received 17 December 2008/ Accepted 8 January 2009
Macrophage migration-inhibitory factor (MIF) is an upstream regulator of innate immunity and a potential molecular link between inflammation and cancer. The unusual structural homology between MIF and certain tautomerases, which includes both a conserved substrate-binding pocket and a catalytic N-terminal proline (Pro1), has fueled speculation that an enzymatic reaction underlies MIF's biologic function. To address the functional role of the MIF tautomerase activity in vivo, we created a knock-in mouse in which the endogenous mif gene was replaced by one encoding a tautomerase-null, Pro1
Gly1 MIF protein (P1G-MIF). While P1G-MIF is completely inactive catalytically, it maintains significant, albeit reduced, binding to its cell surface receptor (CD74) and to the intracellular binding protein JAB1/CSN5. P1G-MIF knock-in mice (mifP1G/P1G) and cells derived from these mice show a phenotype in assays of growth control and tumor induction that is intermediate between those of the wild type (mif+/+) and complete MIF deficiency (mif–/–). These data provide genetic evidence that MIF's intrinsic tautomerase activity is dispensable for this cytokine's growth-regulatory properties and support a role for the N-terminal region in protein-protein interactions.
* Corresponding author. Mailing address: Yale University School of Medicine, Anlyan Center, S525, P.O. Box 208031, 300 Cedar Street, New Haven, CT 06520-8031. Phone: (203) 737-1453. Fax: (203) 785-7053. E-mail: Richard.Bucala{at}Yale.edu
Published ahead of print on 2 January 2009.
Molecular and Cellular Biology, April 2009, p. 1922-1932, Vol. 29, No. 7
0270-7306/09/$08.00+0 doi:10.1128/MCB.01907-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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