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      Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans

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          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.

          Abstract

          In contrast to mammalian cells, C. elegans models can be useful because of cells being post-mitotic in adults. Here the authors show activation of the p38 pathway in cisplatin resistant adult animals and characterise the proteins upstream and downstream of the p38 MAPK signalling pathway that are involved in the cisplatin response.

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          Most cited references72

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          The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences

          The PRoteomics IDEntifications (PRIDE) database ( https://www.ebi.ac.uk/pride/ ) is the world's largest data repository of mass spectrometry-based proteomics data. PRIDE is one of the founding members of the global ProteomeXchange (PX) consortium and an ELIXIR core data resource. In this manuscript, we summarize the developments in PRIDE resources and related tools since the previous update manuscript was published in Nucleic Acids Research in 2019. The number of submitted datasets to PRIDE Archive (the archival component of PRIDE) has reached on average around 500 datasets per month during 2021. In addition to continuous improvements in PRIDE Archive data pipelines and infrastructure, the PRIDE Spectra Archive has been developed to provide direct access to the submitted mass spectra using Universal Spectrum Identifiers. As a key point, the file format MAGE-TAB for proteomics has been developed to enable the improvement of sample metadata annotation. Additionally, the resource PRIDE Peptidome provides access to aggregated peptide/protein evidences across PRIDE Archive. Furthermore, we will describe how PRIDE has increased its efforts to reuse and disseminate high-quality proteomics data into other added-value resources such as UniProt, Ensembl and Expression Atlas.
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            THE GENETICS OF CAENORHABDITIS ELEGANS

            Methods are described for the isolation, complementation and mapping of mutants of Caenorhabditis elegans, a small free-living nematode worm. About 300 EMS-induced mutants affecting behavior and morphology have been characterized and about one hundred genes have been defined. Mutations in 77 of these alter the movement of the animal. Estimates of the induced mutation frequency of both the visible mutants and X chromosome lethals suggests that, just as in Drosophila, the genetic units in C.elegans are large.
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              Universal sample preparation method for proteome analysis.

              We describe a method, filter-aided sample preparation (FASP), which combines the advantages of in-gel and in-solution digestion for mass spectrometry-based proteomics. We completely solubilized the proteome in sodium dodecyl sulfate, which we then exchanged by urea on a standard filtration device. Peptides eluted after digestion on the filter were pure, allowing single-run analyses of organelles and an unprecedented depth of proteome coverage.
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                Author and article information

                Contributors
                gautam.kao@gu.se
                peter.naredi@gu.se
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                20 May 2023
                20 May 2023
                2023
                : 14
                : 2886
                Affiliations
                [1 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, , University of Gothenburg, ; SE413 45 Gothenburg, Sweden
                [2 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Bioinformatics and Data Centre, Sahlgrenska Academy, , University of Gothenburg, Gothenburg, ; SE413 45 Gothenburg, Sweden
                [3 ]GRID grid.1649.a, ISNI 000000009445082X, Department of Surgery, , Sahlgrenska University Hospital, ; SE413 45 Gothenburg, Sweden
                [4 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Present Address: Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, , University of Gothenburg, ; SE413 45 Gothenburg, Sweden
                Author information
                http://orcid.org/0000-0002-7357-2902
                http://orcid.org/0000-0003-0366-1683
                http://orcid.org/0000-0002-1120-8216
                http://orcid.org/0000-0003-1313-3024
                http://orcid.org/0000-0002-5652-0422
                Article
                38568
                10.1038/s41467-023-38568-5
                10199892
                37210583
                ddb08482-aadb-40e8-a31d-5eb05cc5c99f
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 June 2021
                : 9 May 2023
                Funding
                Funded by: Swedish Cancer Society CAN 2018/664 (P.N.) ALF means nr: ALFGBG-722971 (P.N.) Stiftelsen Assar Gabrielssons Fond FB19-44 (DR) Stiftelsen Assar Gabrielssons Fond FB20-32 (DR)
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                © Springer Nature Limited 2023

                Uncategorized
                cell signalling,caenorhabditis elegans,signal transduction,immune cell death,chemotherapy

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