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See detailResolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression.
Lucarelli, Philippe UL; Schilling, Marcel; Kreutz, Clemens et al

in Cell Systems (2017)

Upon stimulation of cells with transforming growth factor beta (TGF-beta), Smad proteins form trimeric complexes and activate a broad spectrum of target genes. It remains unresolved which of the possible ... [more ▼]

Upon stimulation of cells with transforming growth factor beta (TGF-beta), 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. [less ▲]

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See detailDownregulation of the TGF-beta pseudoreceptor BAMBI in non-small cell lung cancer enhances TGF-beta signaling and invasion.
Marwitz, Sebastian; Depner, Sofia; Dvornikov, Dmytro et al

in Cancer research (2016)

Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where ... [more ▼]

Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where curative therapeutic options are lacking. In this study, we identify a targetable mechanism involving TGF-beta elevation that orchestrates tumor progression in this disease. Substantial activation of this pathway was detected in human lung cancer tissues with concomitant downregulation of BAMBI, a negative regulator of the TGF-beta signaling pathway. Alterations of epithelial-to-mesenchymal transition (EMT) marker expression were observed in lung cancer samples compared to tumor-free tissues. Distinct alterations in the DNA methylation of the gene regions encoding TGF-beta pathway components were detected in NSCLC samples compared to tumor-free lung tissues. In particular, epigenetic silencing of BAMBI was identified as a hallmark of NSCLC. Reconstitution of BAMBI expression in NSCLC cells resulted in a marked reduction of TGF-beta-induced EMT, migration and invasion in vitro, along with reduced tumor burden and tumor growth in vivo. In conclusion, our results demonstrate how BAMBI downregulation drives the invasiveness of NSCLC, highlighting TGF-beta signaling as a candidate therapeutic target in this setting. [less ▲]

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