Resolving the combinatorial complexity of Smad protein complex formation and its link to gene expression
Abstract: Upon stimulation of cells with transforming growth factor β (TGF-β), Smad proteins form trimeric complexes and activate a broad spectrum of target genes. It remains unresolved which of the possible Smad complexes are formed in cellular contexts and how these contribute to gene expression. By combining quantitative mass spectrometry with a computational selection strategy, we predict and provide experimental evidence for the three most relevant Smad complexes in the mouse hepatoma cell line Hepa1-6. Utilizing dynamic pathway modeling, we specify the contribution of each Smad complex to the expression of representative Smad target genes, and show that these contributions are conserved in human hepatoma cell lines and primary hepatocytes. We predict, based on gene expression data of patient samples, increased amounts of Smad2/3/4 proteins and Smad2 phosphorylation as hallmarks of hepatocellular carcinoma and experimentally verify this prediction. Our findings demonstrate that modeling approaches can disentangle the complexity of transcription factor complex formation and its impact on gene expression
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Notes
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Cell systems. - 6, 1 (2018) , 75-89.e11, ISSN: 2405-4720
- Event
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Veröffentlichung
- (where)
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Freiburg
- (who)
-
Universität
- (when)
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2019
- Creator
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Lucarelli, Philippe
Schilling, Marcel
Kreutz, Clemens
Vlasov, Artyom
Böhm, Martin Erich
Iwamoto, Nao
Steiert, Bernhard
Lattermann, Susen
Wäsch, Marvin
Stepath, Markus
Matter, Matthias S.
Heikenwälder, Mathias
Hoffmann, Katrin
Deharde, Daniela
Damm, Georg
Seehofer, Daniel
Muciek, Maria
Gretz, Norbert
Lehmann, Wolf-Dieter
Timmer, Jens
Klingmüller, Ursula
- DOI
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10.1016/j.cels.2017.11.010
- URN
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urn:nbn:de:bsz:25-freidok-1450242
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
-
25.03.2025, 1:51 PM CET
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Associated
- Lucarelli, Philippe
- Schilling, Marcel
- Kreutz, Clemens
- Vlasov, Artyom
- Böhm, Martin Erich
- Iwamoto, Nao
- Steiert, Bernhard
- Lattermann, Susen
- Wäsch, Marvin
- Stepath, Markus
- Matter, Matthias S.
- Heikenwälder, Mathias
- Hoffmann, Katrin
- Deharde, Daniela
- Damm, Georg
- Seehofer, Daniel
- Muciek, Maria
- Gretz, Norbert
- Lehmann, Wolf-Dieter
- Timmer, Jens
- Klingmüller, Ursula
- Universität
Time of origin
- 2019
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