title: Endoplasmic reticulum stress-mediated activation of p38 MAPK, Caspase-2 and Caspase-8 leads to abrin-induced apoptosis.
abstract: Abrin from Abrus precatorius plant is a potent protein synthesis inhibitor and induces apoptosis in cells. However, the relationship between inhibition of protein synthesis and apoptosis is not well understood. Inhibition of protein synthesis by abrin can lead to accumulation of unfolded protein in the endoplasmic reticulum causing ER stress. The observation of phosphorylation of eukaryotic initiation factor 2α and upregulation of CHOP (CAAT/enhancer binding protein (C/EBP) homologous protein), important players involved in ER stress signaling by abrin, suggested activation of ER stress in the cells. ER stress is also known to induce apoptosis via stress kinases such as p38 MAPK and JNK. Activation of both the pathways was observed upon abrin treatment and found to be upstream of the activation of caspases. Moreover, abrin-induced apoptosis was found to be dependent on p38 MAPK but not JNK. We also observed that abrin induced the activation of caspase-2 and caspase-8 and triggered Bid cleavage leading to mitochondrial membrane potential loss and thus connecting the signaling events from ER stress to mitochondrial death machinery.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Ritu
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Karande
mesh_terms: D000036:Abrin / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D053143:Caspase 2 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004249:DNA Damage; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000036:Abrin; D048051:p38 Mitogen-Activated Protein Kinases; C490360:CASP2 protein, human; D053143:Caspase 2; D053181:Caspase 8; D003546:Cysteine Endopeptidases