Quantitative phosphoproteomics to unravel the cellular response to chemical stressors with different modes of action
| Autor: | Jesper V. Olsen, Harry Vrieling, Leon H.F. Mullenders, Bharath Sampadi, Alex Pines, Branislav Misovic, Anton J.L. de Groot, Bob van de Water, Stephanie Munk |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Proteome Stress signaling DNA damage Health Toxicology and Mutagenesis Ataxia Telangiectasia Mutated Proteins 010501 environmental sciences Phoshoproteomics Toxicology medicine.disease_cause 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Mice Cyclosporine A Molecular Toxicology medicine Animals Humans Topoisomerase II Inhibitors DNA Breaks Double-Stranded Phosphorylation 0105 earth and related environmental sciences Etoposide Cisplatin Kinase Phosphoproteomics Cell Differentiation General Medicine Cell biology Oxidative Stress Diethyl maleate 030104 developmental biology chemistry Topoisomerase-II Inhibitor DNA Oxidative stress medicine.drug Signal Transduction |
| Zdroj: | Archives of Toxicology Archives of Toxicology, 94(5), 1655-1671. SPRINGER HEIDELBERG Archives of Toxicology, 94, 1655-1671 Sampadi, B, Pines, A, Munk, S, Mišovic, B, de Groot, A J, van de Water, B, Olsen, J V, Mullenders, L H F & Vrieling, H 2020, ' Quantitative phosphoproteomics to unravel the cellular response to chemical stressors with different modes of action ', Archives of Toxicology, vol. 94, pp. 1655-1671 . https://doi.org/10.1007/s00204-020-02712-7 |
| DOI: | 10.1007/s00204-020-02712-7 |
| Popis: | Damage to cellular macromolecules and organelles by chemical exposure evokes activation of various stress response pathways. To what extent different chemical stressors activate common and stressor-specific pathways is largely unknown. Here, we used quantitative phosphoproteomics to compare the signaling events induced by four stressors with different modes of action: the DNA damaging agent: cisplatin (CDDP), the topoisomerase II inhibitor: etoposide (ETO), the pro-oxidant: diethyl maleate (DEM) and the immunosuppressant: cyclosporine A (CsA) administered at an equitoxic dose to mouse embryonic stem cells. We observed major differences between the stressors in the number and identity of responsive phosphosites and the amplitude of phosphorylation. Kinase motif and pathway analyses indicated that the DNA damage response (DDR) activation by CDDP occurs predominantly through the replication-stress-related Atr kinase, whereas ETO triggers the DDR through Atr as well as the DNA double-strand-break-associated Atm kinase. CsA shares with ETO activation of CK2 kinase. Congruent with their known modes of action, CsA-mediated signaling is related to down-regulation of pathways that control hematopoietic differentiation and immunity, whereas oxidative stress is the most prominent initiator of DEM-modulated stress signaling. This study shows that even at equitoxic doses, different stressors induce distinctive and complex phosphorylation signaling cascades. Electronic supplementary material The online version of this article (10.1007/s00204-020-02712-7) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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