Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis

The trichothecene family of mycotoxins inhibit protein synthesis by binding to the ribosomal peptidyltransferase site. Inhibitors of the peptidyltrans ferase reaction (e.g. anisomycin) can trigger a ribotoxic stress response t hat activates c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein k inases, components of a signaling cascade that regulates cell survival in r esponse to stress. We have found that selected trichothecenes strongly acti vate 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 in duction of apoptosis. Among trichothecenes that strongly activate JNK/p38 k inases, induction of apoptosis increases linearly with inhibition of protei n synthesis. Among trichothecenes that strongly inhibit protein synthesis, induction of apoptosis increases linearly with activation of JNK/p38 kinase s. Trichothecenes that inhibit protein synthesis without activating JNK/p38 kinases inhibit the function (i.e. activation of JNK/p38 kinases and induc tion of apoptosis) of apoptotic trichothecenes and anisomycin. Harringtonin e, a structurally unrelated protein synthesis inhibitor that competes with trichothecenes (and anisomycin) for ribosome binding, also inhibits the act ivation 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.