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A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites.
Reich, Stefan; Nguyen, Chi D L; Has, Canan; Steltgens, Sascha; Soni, Himanshu; Coman, Cristina; Freyberg, Moritz; Bichler, Anna; Seifert, Nicole; Conrad, Dominik; Knobbe-Thomsen, Christiane B; Tews, Björn; Toedt, Grischa; Ahrends, Robert; Medenbach, Jan.
Afiliación
  • Reich S; Biochemistry I, University of Regensburg, Regensburg, Germany.
  • Nguyen CDL; Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
  • Has C; Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
  • Steltgens S; Institute for Clinical Chemistry and Laboratory Medicine, Technical University Dresden, Dresden, Germany.
  • Soni H; Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Coman C; Molecular Mechanisms of Tumor Invasion, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Freyberg M; Department of Analytical Chemistry, University of Vienna, Vienna, Austria.
  • Bichler A; Biochemistry I, University of Regensburg, Regensburg, Germany.
  • Seifert N; Biochemistry I, University of Regensburg, Regensburg, Germany.
  • Conrad D; Biochemistry I, University of Regensburg, Regensburg, Germany.
  • Knobbe-Thomsen CB; Biochemistry I, University of Regensburg, Regensburg, Germany.
  • Tews B; Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Toedt G; Molecular Mechanisms of Tumor Invasion, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Ahrends R; AbbVie Deutschland GmbH & Co.KG, Wiesbaden, Germany.
  • Medenbach J; Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Nat Commun ; 11(1): 2936, 2020 06 10.
Article en En | MEDLINE | ID: mdl-32522993
Stress response pathways are critical for cellular homeostasis, promoting survival through adaptive changes in gene expression and metabolism. They play key roles in numerous diseases and are implicated in cancer progression and chemoresistance. However, the underlying mechanisms are only poorly understood. We have employed a multi-omics approach to monitor changes to gene expression after induction of a stress response pathway, the unfolded protein response (UPR), probing in parallel the transcriptome, the proteome, and changes to translation. Stringent filtering reveals the induction of 267 genes, many of which have not previously been implicated in stress response pathways. We experimentally demonstrate that UPR-mediated translational control induces the expression of enzymes involved in a pathway that diverts intermediate metabolites from glycolysis to fuel mitochondrial one-carbon metabolism. Concomitantly, the cells become resistant to the folate-based antimetabolites Methotrexate and Pemetrexed, establishing a direct link between UPR-driven changes to gene expression and resistance to pharmacological treatment.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulón / Respuesta de Proteína Desplegada / Ácido Fólico / Antimetabolitos Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulón / Respuesta de Proteína Desplegada / Ácido Fólico / Antimetabolitos Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido