The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury

Qi, Dake; Atsina, Kwame; Qu, Lintao; Hu, Xiaoyue; Wu, Xiaohong; Xu, Bin; Piecychna, Marta; Leng, Lin; Fingerle‐Rowson, Günter; Zhang, Jiasheng; Bucala, Richard; Young, Lawrence H.

doi:10.1172/jci73061

Cited by 61 publications

(84 citation statements)

References 52 publications

(80 reference statements)

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“…MIF stimulation activates the cardioprotective AMPK pathway during ischemia (Miller et al 2008). Nonetheless, AMPK activation had a greater degree of impairment in CD74 K/K than MIF K/K hearts during ischemia (Qi et al 2014). The sequence or interaction of AKT inhibition and AMPK activation could not be determined in this study.…”

Section: Discussionmentioning

confidence: 76%

“…Stimulation of surface CD74 induces a signaling cascade resulting in AKT activation and cell proliferation (Starlets et al 2006). Furthermore, impaired AMPK activation was observed in the hearts of CD74-knockout mice during ischemia (Qi et al 2014). Decreased AKT Thr 308 phosphorylation was observed following anti-CD74 antibody treatment, while AKT Ser 473 phosphorylation was slightly reduced (Fig.…”

Section: Survival Pathways Involved In Cd74 Modulationmentioning

confidence: 93%

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CD74 expression and its therapeutic potential in thyroid carcinoma

Cheng¹,

Liu²,

Chen³

et al. 2015

Endocrine-Related Cancer

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CD74, the invariant chain of major histocompatibility complex class II, is also a receptor for macrophage migration inhibitory factor (MIF). CD74 and MIF have been associated with tumor progression and metastasis in hematologic and solid tumors. In this study, we found that 60 and 65% of papillary thyroid cancers were positive for CD74 and MIF immunohistochemical staining respectively. Anaplastic thyroid cancer was negative for MIF, but mostly positive for CD74 expression. Normal thyroid tissue and follicular adenomas were negative for CD74 expression. CD74 expression in papillary thyroid cancer was associated with larger tumor size (PZ0.043), extrathyroidal invasion (PZ0.021), advanced TNM stage (PZ0.006), and higher MACIS score (PZ0.026). No clinicopathological parameter was associated with MIF expression. Treatment with anti-CD74 antibody in thyroid cancer cells inhibited cell growth, colony formation, cell migration and invasion, and vascular endothelial growth factor secretion. In contrast, treatment with recombinant MIF induced an increase in cell invasion. Anti-CD74 treatment reduced AKT phosphorylation and stimulated AMPK activation. Our findings suggest that CD74 overexpression in thyroid cancer is associated with advanced tumor stage and may serve as a therapeutic target.

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Section: Discussionmentioning

confidence: 76%

Section: Survival Pathways Involved In Cd74 Modulationmentioning

confidence: 93%

CD74 expression and its therapeutic potential in thyroid carcinoma

Cheng¹,

Liu²,

Chen³

et al. 2015

Endocrine-Related Cancer

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“…D-Dopachrome tautomerase, an orthologous MIF protein that binds CD74, may have therapeutic potential as well (65)(66)(67)(68). Finally, these data should prompt investigation into the potential protective role in ARDS of variant MIF alleles, which occur commonly in the human population and have been linked to the severity of other inflammatory or infectious conditions of the lung (e.g., asthma, pneumonia, and tuberculosis).…”

Section: Discussionmentioning

confidence: 99%

Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury

et al. 2015

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Exposure to hyperoxia results in acute lung injury. A pathogenic consequence of hyperoxia is endothelial injury. Macrophage migration inhibitory factor (MIF) has a cytoprotective effect on lung endothelial cells; however, the mechanism is uncertain. We postulate that the MIF receptor CD74 mediates this protective effect. Using adult wild-type (WT), MIF-deficient (Mif 2/2 ), CD74-deficient (Cd74 2/2 ) mice and MIF receptor inhibitor treated mice, we report that MIF deficiency or inhibition of MIF receptor binding results in increased sensitivity to hyperoxia. Mif 2/2 and Cd74 2/2 mice demonstrated decreased median survival following hyperoxia compared to WT mice. Mif 2/2 mice demonstrated an increase in bronchoalveolar protein (48%) and lactate dehydrogenase (LDH) (68%) following 72 hours of hyperoxia. Similarly, treatment with MIF receptor antagonist resulted in a 59% and 91% increase in bronchoalveolar lavage protein and LDH, respectively. Inhibition of CD74 in primary murine lung endothelial cells (MLECs) abrogated the protective effect of MIF, including decreased hyperoxia-mediated AKT phosphorylation and a 20% reduction in the antiapoptotic effect of exogenous MIF. Treatment with MIF decreased hyperoxia-mediated H2AX phosphorylation in a CD74-dependent manner. These data suggest that therapeutic manipulation of the MIF-CD74 axis in lung endothelial cells may be a novel approach to protect against acute oxidative stress.-Sauler,

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“…Lawrence Young (Yale) discussed AMPK regulation of mitochondrial function after ischemia/reperfusion. He also spoke about the therapeutic potential of D-dopachrome tautomerase (DDT), a novel secreted protein from cardiomyocytes which has important autocrine/paracrine actions, for preventing cardiac injury during ischemia (Qi et al, 2014). Interestingly, the cardioprotective effect of DDT requires downstream AMPK activation via a calcium-dependent, energyindependent mechanism implicating CaMKKb as the primary upstream kinase.…”

mentioning

confidence: 99%