RRC ID 80778
Author Raj D, Kraish B, Martikainen J, Podraza-Farhanieh A, Kao G, Naredi P.
Title Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans.
Journal Nat Commun
Abstract Cisplatin kills proliferating cells via DNA damage but also has profound effects on post-mitotic cells in tumors, kidneys, and neurons. However, the effects of cisplatin on post-mitotic cells are still poorly understood. Among model systems, C. elegans adults are unique in having completely post-mitotic somatic tissues. The p38 MAPK pathway controls ROS detoxification via SKN-1/NRF and immune responses via ATF-7/ATF2. Here, we show that p38 MAPK pathway mutants are sensitive to cisplatin, but while cisplatin exposure increases ROS levels, skn-1 mutants are resistant. Cisplatin exposure leads to phosphorylation of PMK-1/MAPK and ATF-7 and the IRE-1/TRF-1 signaling module functions upstream of the p38 MAPK pathway to activate signaling. We identify the response proteins whose increased abundance depends on IRE-1/p38 MAPK activity as well as cisplatin exposure. Four of these proteins are necessary for protection from cisplatin toxicity, which is characterized by necrotic death. We conclude that the p38 MAPK pathway-driven proteins are crucial for adult cisplatin resilience.
Volume 14(1)
Pages 2886
Published 2023-5-20
DOI 10.1038/s41467-023-38568-5
PII 10.1038/s41467-023-38568-5
PMID 37210583
PMC PMC10199892
MeSH Activating Transcription Factors Animals Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / metabolism Cisplatin / metabolism Cisplatin / toxicity MAP Kinase Signaling System Reactive Oxygen Species / metabolism Signal Transduction p38 Mitogen-Activated Protein Kinases / genetics p38 Mitogen-Activated Protein Kinases / metabolism
C.elegans tm2457 tm4063