Trichothecene Mycotoxins Trigger a Ribotoxic Stress Response That Activates c-Jun N-terminal Kinase and p38 Mitogen-activated Protein Kinase and Induces Apoptosis

• DOI: 10.1074/jbc.274.20.13985
• Publication Date: 2002-07-26T14:56:47Z
• Authors: Victor I. Shifrin; Paul Anderson
• Keywords: Protein Synthesis Inhibitors; 0301 basic medicine; Harringtonines; Caspase 3; Emetine; JNK Mitogen-Activated Protein Kinases; Apoptosis; DNA Fragmentation; p38 Mitogen-Activated Protein Kinases; 3. Good health; Enzyme Activation; Jurkat Cells; Kinetics; Oxidative Stress; T-2 Toxin; 03 medical and health sciences; Caspases; Calcium-Calmodulin-Dependent Protein Kinases; Humans; Mitogen-Activated Protein Kinases; Trichothecenes; Ribosomes; Anisomycin

The trichothecene family of mycotoxins inhibit protein synthesis by binding to the ribosomal peptidyltransferase site. Inhibitors of the peptidyltransferase reaction (e.g. anisomycin) can trigger a ribotoxic stress response that activates c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinases, components of a signaling cascade that regulates cell survival in response to stress. We have found that selected trichothecenes strongly activate JNK/p38 kinases and induce rapid apoptosis in Jurkat T cells. Although the ability of individual trichothecenes to inhibit protein synthesis and activate JNK/p38 kinases are dissociable, both effects contribute to the induction of apoptosis. Among trichothecenes that strongly activate JNK/p38 kinases, induction of apoptosis increases linearly with inhibition of protein synthesis. Among trichothecenes that strongly inhibit protein synthesis, induction of apoptosis increases linearly with activation of JNK/p38 kinases. Trichothecenes that inhibit protein synthesis without activating JNK/p38 kinases inhibit the function (i.e. activation of JNK/p38 kinases and induction of apoptosis) of apoptotic trichothecenes and anisomycin. Harringtonine, a structurally unrelated protein synthesis inhibitor that competes with trichothecenes (and anisomycin) for ribosome binding, also inhibits the activation of JNK/p38 kinases and induction of apoptosis by trichothecenes and anisomycin. Taken together, these results implicate the peptidyltransferase site as a regulator of both JNK/p38 kinase activation and apoptosis.