INSIGHTS INTO THE ROLE OF GRIM-19 IN MITOCHONDRIAL FUNCTION AND INTERFERON -RETINOIC ACID INDUCED CELL DEATH PATHWAY

Abstract

INTERFERONS (IFN) ARE CYTOKINES THAT REGULATE ANTI TUMOUR, IMMUNE AND ANTI VIRAL RESPONSES IN VERTEBRATES. RETINOIC ACID (RA) IS A METABOLITE OF VITAMIN A THAT HAS PROFOUND EFFECTS ON METABOLISM, CELL GROWTH AND DIFFERENTIATION. THE COMBINATORIAL THERAPEUTIC EFFECT OF IFN/RA HAS BEEN SHOWN TO BE MORE POTENT IN FIGHTING CANCER CELLS THAN THAT OF EITHER DRUG ALONE. GRIM-19 IS A PROTEIN THAT WAS IDENTIFIED TO BE ONE OF THE DOWNSTREAM PLAYERS OF THE IFN/RA INDUCED CELL DEATH PATHWAY. THE RESULTS OF THIS STUDY CONFIRM THE LOCALIZATION OF GRIM-19 TO BE IN THE INNER MITOCHONDRIAL MEMBRANE AND SHOW THAT THOUGH GRIM-19 OVER EXPRESSION OR KNOCK DOWN (KD) DOES NOT AFFECT THE MORPHOLOGY OR DYNAMICS OF MITOCHONDRIA, GRIM-19 KNOCK DOWN INCREASES REACTIVE OXYGEN SPECIES (ROS) PRODUCTION IN CELLS. MOREOVER, THREE CANCER DERIVED MUTANT FORMS OF GRIM-19 FAIL TO RESCUE THE INCREASE IN ROS CAUSED BY THE KNOCK DOWN.