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Quantitative phosphoproteomics to unravel the cellular response to chemical stressors with different modes of action.
Sampadi, Bharath; Pines, Alex; Munk, Stephanie; Misovic, Branislav; de Groot, Anton J; van de Water, Bob; Olsen, Jesper V; Mullenders, Leon H F; Vrieling, Harry.
Afiliação
  • Sampadi B; Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
  • Pines A; Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
  • Munk S; Novo Nordisk Foundation Center for Protein Research, Proteomics Program, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3b, 2200, Copenhagen, Denmark.
  • Misovic B; Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
  • de Groot AJ; Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
  • van de Water B; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
  • Olsen JV; Novo Nordisk Foundation Center for Protein Research, Proteomics Program, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3b, 2200, Copenhagen, Denmark.
  • Mullenders LHF; Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
  • Vrieling H; Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan.
Arch Toxicol ; 94(5): 1655-1671, 2020 05.
Article em En | MEDLINE | ID: mdl-32189037
ABSTRACT
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteoma Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteoma Idioma: En Ano de publicação: 2020 Tipo de documento: Article