The MIF homologue D-dopachrome tautomerase promotes COX-2 expression through β-catenin-dependent and -independent mechanisms.
The cytokine/growth factor, macrophage migration inhibitory factor (MIF), contributes to pathologies associated with immune, inflammatory, and neoplastic disease processes. Several studies have shown an important contributing role for MIF-dependent COX-2 expression in the progression of these disorders. We now report that the MIF homologue, D-dopachrome tautomerase (D-DT), is both sufficient and necessary for maximal COX-2 expression in colorectal adenocarcinoma cell lines. D-DT-dependent COX-2 transcription is mediated in part by β-catenin protein stabilization and subsequent transcription. Also contributing to D-DTs regulation of COX-2 expression are the activities of both c-jun-N-terminal kinase and the MIF-interacting protein, Jab1/CSN5. Interestingly, D-DT-dependent β-catenin stabilization is regulated by COX-2 expression, suggesting the existence of an amplification loop between COX-2- and β-catenin-mediated transcription in these cells. Because both COX-2- and β-catenin-mediated transcription are important contributors to colorectal cancer (CRC) disease maintenance and progression, these findings suggest a unique and novel regulatory role for MIF family members in CRC pathogenesis.
University of Louisville, Clinical and Translational Research Building, 505 S. Hancock St., Suite 404, Louisville, KY 40202, USA.
Dan
D
Xin
Beatriz E
BE
Rendon
Ming
M
Zhao
Millicent
M
Winner
Arlixer
A
McGhee Coleman
Robert A
RA
Mitchell
D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048670:MAP Kinase Kinase 4; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C042501:dopachrome isomerase