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Arsenic, a metalloid with cytotoxic and carcinogenic effects related to the disruption of glutathione homeostasis, induces the expression of ATF4, a central transcription factor in the cellular stress response. However, the interplay between factors downstream of ATF4 is incompletely understood. In this article, we investigate the role of Tribbles homolog 3 (TRIB3), a regulatory member of the ATF4 pathway, in determining cell sensitivity to arsenite. Our results show that arsenite potently upregulates Trib3 mRNA and protein in an ATF4-dependent manner in mouse embryonic fibroblasts. Trib3-deficient cells display increased susceptibility to arsenite-induced cell death, which is rescued by re-expressing TRIB3. In cells lacking TRIB3, arsenite stress leads to markedly elevated mRNA and protein levels of Chac1, a gene that encodes a glutathione-degrading enzyme and is not previously known to be repressed by TRIB3. Analysis of the Chac1 promoter identified two regulatory elements that additively mediate the induction of Chac1 by arsenite and ATF4, as well as the robust suppression of Chac1 by TRIB3. Crucially, Chac1 silencing enhances glutathione levels and eliminates the increased susceptibility of Trib3-deficient cells to arsenite stress. Moreover, Trib3-deficient cells demonstrate an increased rate of glutathione consumption, which is abolished by Chac1 knockdown. Taken together, these data indicate that excessive Chac1 expression is detrimental to arsenite-treated cell survival and that TRIB3 is critical for restraining the pro-death potential of Chac1 during arsenite stress, representing a novel mechanism of cell viability regulation that occurs within the ATF4 pathway.
Pubmed ID: 27526673 RIS Download
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A national mouse monoclonal antibody generating resource for biochemical and immunohistochemical applications in mammalian brain. NeuroMabs are generated from mice immunized with synthetic and recombinant immunogens corresponding to components of the neuronal proteome as predicted from genomic and other large-scale cloning efforts. Comprehensive biochemical and immunohistochemical analyses of human, primate and non-primate mammalian brain are incorporated into the initial NeuroMab screening procedure. This yields a subset of mouse mAbs that are optimized for use in brain (i.e. NeuroMabs): for immunocytochemical-based imaging studies of protein localization in adult, developing and pathological brain samples, for biochemical analyses of subunit composition and post-translational modifications of native brain proteins, and for proteomic analyses of native brain protein networks. The NeuroMab facility was initially funded with a five-year U24 cooperative grant from NINDS and NIMH. The initial goal of the facility for this funding period is to generate a library of novel NeuroMabs against neuronal proteins, initially focusing on membrane proteins (receptors/channels/transporters), synaptic proteins, other neuronal signaling molecules, and proteins with established links to disease states. The scope of the facility was expanded with supplements from the NIH Blueprint for Neuroscience Research to include neurodevelopmental targets, the NIH Roadmap for Medical Research to include epigenetics targets, and NIH Office of Rare Diseases Research to include rare disease targets. These NeuroMabs will then be produced on a large scale and made available to the neuroscience research community on an inexpensive basis as tissue culture supernatants or purified immunoglobulin by Antibodies Inc. The UC Davis/NIH NeuroMab Facility makes NeuroMabs available directly to end users and is unable to accommodate sales to distributors for third party distribution. Note, NeuroMab antibodies are now offered through antibodiesinc.
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