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TNFα activation of PKCδ, mediated by NFκB and ER stress,cross-talks with the insulin signaling cascade
Authors:Michael W Greene  Mary S Ruhoff  Christine M Burrington  Robert S Garofalo  Stephen J Oreña
Institution:1. Bassett Research Institute, Mary Imogene Bassett Hospital, Cooperstown, NY 13326, United States;2. Pfizer Inc., Global Research and Development, Groton, Connecticut 06340, United States;1. Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA;2. Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA;3. Marlene Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA;4. Department of Pharmaceutical sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA;5. Genomic Core Facility, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA;6. Department of Cancer Biology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, PA 19107, USA;1. Institute of Animal Science, Physiology & Hygiene Unit, University of Bonn, 53115 Bonn, Germany;2. Clinic for Cattle, University of Veterinary Medicine, D-30173 Hannover, Germany;3. Institute of Animal Nutrition, Friedrich-Loeffler-Institute (FLI), Federal Research Institute for Animal Health, 38116 Braunschweig, Germany;4. Institute of Nutritional Physiology ‘Oskar Kellner’, Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany;1. State University of New York at Albany, Behavioral Neuroscience and Center for Neuroscience Research, Albany, NY, United States;2. The College of Saint Rose, Department of Psychology, Albany, NY, United States
Abstract:TNFα plays key roles in the regulation of inflammation, cell death, and proliferation and its signaling cascade cross-talks with the insulin signaling cascade. PKCδ, a novel PKC isoform, is known to participate in proximal TNFα signaling events. However, it has remained unclear whether PKCδ plays a role in distal TNFα signaling events. Here we demonstrate that PKCδ is activated by TNFα in a delayed fashion that is temporally associated with JNK activation. To investigate the signaling pathways activating PKCδ and JNK, we used pharmacological and genetic inhibitors of NFκB. We found that inhibition of NFκB attenuated PKCδ and JNK activations. Further analysis revealed that ER stress contributes to TNFα-stimulated PKCδ and JNK activations. To investigate the role of PKCδ in TNFα action, we used 29-mer shRNAs to silence PKCδ expression. A reduction of ~90% in PKCδ protein levels reduced TNFα-stimulated stress kinase activation, including JNK. Further, PKCδ was necessary for thapsigargin-stimulated JNK activation. Because thapsigargin is a potent inducer of ER stress, we determined whether PKCδ was necessary for induction of the UPR. Indeed, a reduction in PKCδ protein levels reduced thapsigargin-stimulated CHOP induction, a hallmark of the UPR, but not BiP/GRP78 induction, suggesting that PKCδ does not globally regulate the UPR. Next, the role of PKCδ in TNFα mediated cross-talk with the insulin signaling pathway was investigated in cells expressing human IRS-1 and a 29-mer shRNA to silence PKCδ expression. We found that a reduction in PKCδ protein levels reversed the TNFα-mediated reduction in insulin-stimulated IRS-1 Tyr phosphorylation, Akt activation, and glycogen synthesis. In addition, TNFα-stimulated IRS protein Ser/Thr phosphorylation and degradation were blocked. Our results indicate that: 1) NFκB and ER stress contribute in part to PKCδ activation; 2) PKCδ plays a key role in the propagation of the TNFα signal; and 3) PKCδ contributes to TNFα-induced inhibition of insulin signaling events.
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