Abstract
The mechanisms of cadmium (Cd) resistance are complex and not sufficiently understood. The present study, therefore, aimed at assessing the roles of important components of stress-signaling pathways and of ABC transporters under severe Cd stress in Caenorhabditis elegans. Survival assays on mutant and control animals revealed a significant promotion of Cd resistance by the PMK-1 p38 MAP kinase, the transcription factor DAF-16/FoxO, and the ABC transporter MRP-1. Transcriptome profiling by RNA-Seq on wild type and a pmk-1 mutant under control and Cd stress conditions revealed, inter alia, a PMK-1-dependent promotion of gene expression for the translational machinery. PMK-1 also promoted the expression of target genes of the transcription factors SKN-1/Nrf and DAF-16 in Cd-stressed animals, which included genes for molecular chaperones or immune proteins. Gene expression studies by qRT-PCR confirmed the positive effects of PMK-1 on DAF-16 activity under Cd stress and revealed negative effects of DAF-16 on the expression of genes for MRP-1 and DAF-15/raptor. Additional studies on pmk-1 RNAi-treated wild type and mutant strains provided further information on the effects of PMK-1 on SKN-1 and DAF-16, which resulted in a model of these relationships. The results of this study demonstrate a central role of PMK-1 for the processing of cellular responses to abiotic and biotic stressors, with the promoting effects of PMK-1 on Cd resistance mostly mediated by the transcription factors SKN-1 and DAF-16.
Highlights
The heavy metal cadmium (Cd) poses a serious threat to organisms and cells by promoting the formation of reactive oxygen species (ROS; Wang et al 2004) and impairing antioxidant systems, DNA repair, RNA/protein synthesis, cell cycle, differentiation, and proliferation (Beyersmann and Hechtenberg 1997; Company et al 2004)
The results of this study demonstrate a central role of PMK-1- or DAF-16-overexpressing strains (PMK-1) for the processing of cellular responses to abiotic and biotic stressors, with the promoting effects of PMK-1 on Cd resistance mostly mediated by the transcription factors SKN-1 and DAF-16
After determining the survival rates of synchronized young adult WT worms after 24 h at different Cd concentrations (Fig. 1a), 10 mmol/L CdCl2 was chosen as the standard test, because it provided a sufficient margin to test for variations in stress resistance
Summary
The heavy metal cadmium (Cd) poses a serious threat to organisms and cells by promoting the formation of reactive oxygen species (ROS; Wang et al 2004) and impairing antioxidant systems, DNA repair, RNA/protein synthesis, cell cycle, differentiation, and proliferation (Beyersmann and Hechtenberg 1997; Company et al 2004). The JNK-like MAPK KGB-1 of C. elegans participates in the response to heavy metal stress (Koga et al 2000; Mizuno et al 2008; Fujiki et al 2010), which involves phosphorylation of the transcription factor FOS-1 and the regulation of two so far known genes (kreg-1, -2; Hattori et al 2013). PMK-1 is especially known for its participation in pathogen resistance mechanisms (Huffman et al 2004; Troemel et al 2006; Bolz et al 2010) and oxidative or heat stress responses (An et al 2005; Mertenskötter et al.2012). PMK-1-dependent signal processing includes (1) activation of the Nrf-like transcription factor SKN-1 (Inoue et al 2005), which is a major regulator of genes for detoxification and antioxidant defense, (2) PMK-1 nuclear translocation (Mertenskötter et al 2012), and (3) deactivation of the transcriptional repressor ATF-7 in context with pathogen resistance mechanisms (Shivers et al 2010)
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