Dysregulated D-dopachrome tautomerase, a hypoxia-inducible factor-dependent gene, cooperates with macrophage migration inhibitory factor in renal tumorigenesis.

The Journal of Biological Chemistry
Vinay PasupuletiS M Welford

Abstract

Clear cell renal cell carcinomas (ccRCCs) are characterized by biallelic loss of the von Hippel-Lindau tumor suppressor and subsequent constitutive activation of the hypoxia-inducible factors, whose transcriptional programs dictate major phenotypic attributes of kidney tumors. We recently described a role for the macrophage migration inhibitory factor (MIF) in ccRCC as an autocrine-signaling molecule with elevated expression in tumor tissues and in the circulation of patients that has potent tumor cell survival effects. MIF is a pleiotropic cytokine implicated in a variety of diseases and cancers and is the target of both small molecule and antibody-based therapies currently in clinical trials. Recent work by others has described D-dopachrome tautomerase (DDT) as a functional homologue of MIF with a similar genomic structure and expression patterns. Thus, we sought to determine a role for DDT in renal cancer. We find that DDT expression mirrors MIF expression in ccRCC tumor sections with high correlation and that, mechanistically, DDT is a novel hypoxia-inducible gene and direct target of HIF1α and HIF2α. Functionally, DDT and MIF demonstrate a significant overlap in controlling cell survival, tumor formation, and tumor and end...Continue Reading

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Citations

Jun 17, 2014·PloS One·Stephanie E BrockRobert A Mitchell
Mar 7, 2015·European Journal of Medicinal Chemistry·Emma S SpencerJoel D A Tyndall
Oct 4, 2014·Cellular Signalling·Robert A Mitchell, Kavitha Yaddanapudi
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Jan 23, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Maor SaulerPatty J Lee
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Sep 6, 2019·JCI Insight·Yina MaLawrence H Young
Jun 10, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yoko YoshihisaTadamichi Shimizu

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