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Transforming growth factor ? inhibits bone morphogenetic protein-induced transcription through novel phosphorylated Smad1/5-Smad3 complexes.

ABSTRACT: In vivo cells receive simultaneous signals from multiple extracellular ligands and must integrate and interpret them to respond appropriately. Here we investigate the interplay between pathways downstream of two transforming growth factor ? (TGF-?) superfamily members, bone morphogenetic protein (BMP) and TGF-?. We show that in multiple cell lines, TGF-? potently inhibits BMP-induced transcription at the level of both BMP-responsive reporter genes and endogenous BMP target genes. This inhibitory effect requires the TGF-? type I receptor ALK5 and is independent of new protein synthesis. Strikingly, we show that Smad3 is required for TGF-?'s inhibitory effects, whereas Smad2 is not. We go on to demonstrate that TGF-? induces the formation of complexes comprising phosphorylated Smad1/5 and Smad3, which bind to BMP-responsive elements in vitro and in vivo and mediate TGF-?-induced transcriptional repression. Furthermore, loss of Smad3 confers on TGF-? the ability to induce transcription via BMP-responsive elements. Our results therefore suggest that not only is Smad3 important for mediating TGF-?'s inhibitory effects on BMP signaling but it also plays a critical role in restricting the transcriptional output in response to TGF-?.

SUBMITTER: Gronroos E

PROVIDER: S-EPMC3416179 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Transforming growth factor β inhibits bone morphogenetic protein-induced transcription through novel phosphorylated Smad1/5-Smad3 complexes.

Grönroos Eva E Kingston Isabel J IJ Ramachandran Anassuya A Randall Rebecca A RA Vizán Pedro P Hill Caroline S CS

Molecular and cellular biology 20120521 14

In vivo cells receive simultaneous signals from multiple extracellular ligands and must integrate and interpret them to respond appropriately. Here we investigate the interplay between pathways downstream of two transforming growth factor β (TGF-β) superfamily members, bone morphogenetic protein (BMP) and TGF-β. We show that in multiple cell lines, TGF-β potently inhibits BMP-induced transcription at the level of both BMP-responsive reporter genes and endogenous BMP target genes. This inhibitory ...[more]

PMID: 22615489

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Project description:Gastric carcinoma is one of the most common human malignancies and remains the second leading cause of cancer-associated mortality worldwide. Gastric carcinoma is characterized by early-stage metastasis and is typically diagnosed in the advanced stage. Previous results have indicated that bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) overexpression has been demonstrated to inhibit growth and metastasis of gastric cancer cells. However, the molecular mechanisms of the BAMBI-mediated signaling pathway in the progression of gastric cancer are poorly understood. In the present study, to assess whether BAMBI overexpression inhibited the growth and aggressiveness of gastric carcinoma cells through regulation of transforming growth factor (TGF)-β/epithelial-mesenchymal transition (EMT) signaling pathway, the growth and metastasis of gastric carcinoma cells were analyzed following BAMBI overexpression and knockdown in vitro and in vivo. Molecular changes in the TGF-β/EMT signaling pathway were studied in gastric carcinoma cells following BAMBI overexpression and knockdown. DNA methylation of the gene regions encoding the TGF-β/EMT signaling pathway was investigated in gastric carcinoma cells. Tumor growth in tumor-bearing mice was analyzed after mice were subjected to endogenous overexpression of BAMBI. Results indicated that BAMBI overexpression significantly inhibited gastric carcinoma cell growth and aggressiveness, whereas knockdown of BAMBI significantly promoted its growth and metastasis compared with the control (P<0.01). The TGF-β/EMT signaling pathway was downregulated in BAMBI-overexpressed gastric carcinoma cells; however, signaling was promoted following BAMBI knockdown. In addition, it was observed that BAMBI overexpression significantly downregulated the DNA methylation of the gene regions encoding the TGF-β/EMT signaling pathway (P<0.01). Furthermore, RNA interference-mediated BAMBI overexpression also promoted apoptosis in gastric cancer cells and significantly inhibited growth of gastric tumors in murine xenografts (P<0.01). In conclusion, the present findings suggest that BAMBI overexpression inhibited the TGF-β/EMT signaling pathway and suppressed the invasiveness of gastric tumors, suggesting BAMBI may be a potential target for the treatment of gastric carcinoma via regulation of the TGF-β/EMT signaling pathway.

Dataset Information

Transforming growth factor ? inhibits bone morphogenetic protein-induced transcription through novel phosphorylated Smad1/5-Smad3 complexes.

Publications

Transforming growth factor β inhibits bone morphogenetic protein-induced transcription through novel phosphorylated Smad1/5-Smad3 complexes.

Similar Datasets

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