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Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics.
Chang, Yun-Chien; Gnann, Christian; Steimbach, Raphael R; Bayer, Florian P; Lechner, Severin; Sakhteman, Amirhossein; Abele, Miriam; Zecha, Jana; Trendel, Jakob; The, Matthew; Lundberg, Emma; Miller, Aubry K; Kuster, Bernhard.
Afiliação
  • Chang YC; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany.
  • Gnann C; Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden.
  • Steimbach RR; Cancer Drug Development, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany; Biosciences Faculty, Heidelberg University, Heidelberg, Baden-Württemberg, Germany.
  • Bayer FP; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany.
  • Lechner S; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany.
  • Sakhteman A; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany.
  • Abele M; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany; Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany.
  • Zecha J; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany.
  • Trendel J; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany.
  • The M; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany.
  • Lundberg E; Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden; Department of Bioengineering, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA.
  • Miller AK; Cancer Drug Development, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Baden-Württemberg, Germany.
  • Kuster B; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany. Electronic address: kuster@tum.de.
Cell Rep ; 43(6): 114272, 2024 Jun 25.
Article em En | MEDLINE | ID: mdl-38795348
ABSTRACT
Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), and multiple myeloma, but many aspects of their cellular mechanism of action (MoA) and substantial toxicity are not well understood. To shed more light on how KDACis elicit cellular responses, we systematically measured dose-dependent changes in acetylation, phosphorylation, and protein expression in response to 21 clinical and pre-clinical KDACis. The resulting 862,000 dose-response curves revealed, for instance, limited cellular specificity of histone deacetylase (HDAC) 1, 2, 3, and 6 inhibitors; strong cross-talk between acetylation and phosphorylation pathways; localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs); an underappreciated role of acetylation in protein structure; and a shift in EP300 protein abundance between the cytoplasm and the nucleus. This comprehensive dataset serves as a resource for the investigation of the molecular mechanisms underlying KDACi action in cells and can be interactively explored online in ProteomicsDB.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteômica / Inibidores de Histona Desacetilases Limite: Humans Idioma: En Revista: Cell Rep Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteômica / Inibidores de Histona Desacetilases Limite: Humans Idioma: En Revista: Cell Rep Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha