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      Negative regulation of AMP-activated protein kinase (AMPK) activity by macrophage migration inhibitory factor (MIF) family members in non-small cell lung carcinomas.

      The Journal of Biological Chemistry

      AMP-Activated Protein Kinases, genetics, metabolism, Acetylcysteine, pharmacology, Antigens, Differentiation, B-Lymphocyte, Carcinoma, Non-Small-Cell Lung, pathology, Cell Line, Tumor, Deoxyglucose, Enzyme Activation, drug effects, Free Radical Scavengers, Glucose, pharmacokinetics, Histocompatibility Antigens Class II, Humans, Immunoblotting, Intramolecular Oxidoreductases, Lung Neoplasms, Macrophage Migration-Inhibitory Factors, Mutation, Oxidation-Reduction, Phosphorylation, Protein-Serine-Threonine Kinases, RNA Interference, Reactive Oxygen Species, antagonists & inhibitors, Signal Transduction, TOR Serine-Threonine Kinases

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          Abstract

          AMP-activated protein kinase (AMPK) is a nutrient- and metabolic stress-sensing enzyme activated by the tumor suppressor kinase, LKB1. Because macrophage migration inhibitory factor (MIF) and its functional homolog, d-dopachrome tautomerase (d-DT), have protumorigenic functions in non-small cell lung carcinomas (NSCLCs) but have AMPK-activating properties in nonmalignant cell types, we set out to investigate this apparent paradox. Our data now suggest that, in contrast to MIF and d-DTs AMPK-activating properties in nontransformed cells, MIF and d-DT act cooperatively to inhibit steady-state phosphorylation and activation of AMPK in LKB1 wild type and LKB1 mutant human NSCLC cell lines. Our data further indicate that MIF and d-DT, acting through their shared cell surface receptor, CD74, antagonize NSCLC AMPK activation by maintaining glucose uptake, ATP production, and redox balance, resulting in reduced Ca(2+)/calmodulin-dependent kinase kinase β-dependent AMPK activation. Combined, these studies indicate that MIF and d-DT cooperate to inhibit AMPK activation in an LKB1-independent manner.

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          Author and article information

          Journal
          22988252
          3488063
          10.1074/jbc.M112.378299

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