DACH1 inhibits TGF-beta signaling through binding Smad4
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ABSTRACT:
PROVIDER: PRJNA87633 | ENA |
REPOSITORIES: ENA
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Project description:The vertebrate homologues of Drosophila dachsund, DACH1 and DACH2, have been implicated as important regulatory genes in development. DACH1 plays a role in retinal and pituitary precursor cell proliferation and DACH2 plays a specific role in myogenesis. DACH proteins contain a domain (DS-domain) that is conserved with the proto-oncogenes Ski and Sno. Since the Ski/Sno proto-oncogenes repress AP-1 and SMAD signaling, we hypothesized that DACH1 might play a similar cellular function. Herein, DACH1 was found to be expressed in breast cancer cell lines and to inhibit TGF-beta induced apoptosis. DACH1 repressed TGF-beta induction of AP-1 and Smad signaling in gene reporter assays and repressed endogenous TGF-beta responsive genes by microarray analyses. DACH1 bound to endogenous NCoR and Smad4 in cultured cells and DACH1 co-localized with NCoR in nuclear dot-like structures. NCoR enhanced DACH1 repression and the repression of TGF-beta-induced AP-1 or Smad-signaling by DACH1 required the DACH1 DS domain. The DS-domain of DACH was sufficient for NCoR-binding at a Smad4-binding site. Smad4 was required for DACH1 repression of Smad signaling. In Smad4 null HTB-134 cells, DACH1 inhibited the activation of SBE-4 reporter activity induced by Smad2 or Smad3 only in the presence of Smad4. DACH1 participates in the negative regulation of TGF-beta signaling by interacting with NCoR and Smad4. Keywords: other
2003-10-15 | GSE685 | GEO
Project description:The vertebrate homologues of Drosophila dachsund, DACH1 and DACH2, have been implicated as important regulatory genes in development. DACH1 plays a role in retinal and pituitary precursor cell proliferation and DACH2 plays a specific role in myogenesis. DACH proteins contain a domain (DS-domain) that is conserved with the proto-oncogenes Ski and Sno. Since the Ski/Sno proto-oncogenes repress AP-1 and SMAD signaling, we hypothesized that DACH1 might play a similar cellular function. Herein, DACH1 was found to be expressed in breast cancer cell lines and to inhibit TGF-beta induced apoptosis. DACH1 repressed TGF-beta induction of AP-1 and Smad signaling in gene reporter assays and repressed endogenous TGF-beta responsive genes by microarray analyses. DACH1 bound to endogenous NCoR and Smad4 in cultured cells and DACH1 co-localized with NCoR in nuclear dot-like structures. NCoR enhanced DACH1 repression and the repression of TGF-beta-induced AP-1 or Smad-signaling by DACH1 required the DACH1 DS domain. The DS-domain of DACH was sufficient for NCoR-binding at a Smad4-binding site. Smad4 was required for DACH1 repression of Smad signaling. In Smad4 null HTB-134 cells, DACH1 inhibited the activation of SBE-4 reporter activity induced by Smad2 or Smad3 only in the presence of Smad4. DACH1 participates in the negative regulation of TGF-beta signaling by interacting with NCoR and Smad4.
2007-07-19 | E-GEOD-685 | biostudies-arrayexpress
Project description:TGF-β signaling is known to be very much dependent on the formation of Smad2/3-Smad4 transcription regulatory complexes. However, the signaling functions of Smad2/3-Smad4 in TGF-β-induced responses are obscure as TGF-β also initiates a number of other signaling pathways. In this study, we systematically assessed the contribution of TGF-β-Smad2/3-Smad4 signaling to target gene transcription. Individual Smads were selectively knocked down in Hep3B cells by stable RNA interference (RNAi). We identified TGF-β-responsive genes using genome-wide oligonucleotide microarrays and confirmed their dependency on Smad2, Smad3 or Smad4 by the combination of RNAi and microarray assay. The major finding from our microarray analysis was that of the 2039 target genes seen to be regulated via TGF-β induction, 190 were differentially transcriptionally controlled by Smad2-Smad4 and Smad3-Smad4 signaling and the latter control mechanism appeared to be functionally more important. We also found evidence of competition between Smad2 and Smad3 for their activation when controlling the transcription of target genes. Keywords: cell type comparison
2006-11-14 | GSE6242 | GEO
Project description:The tumor suppressive effects of TGF-β are classically associated with the activation of the “canonical” SMAD-mediated pathway, whereas its oncogenic effects are largely attributed to its “non-canonical signaling”. We herein provide evidence of an oncogenic effect for SMAD2 and 3 in response to TGF-β in SMAD4-null cancer cells. Using the CRISPR/Cas9 technology, we report that simultaneous knockout of Smad2 and 3 in Smad4-negative pancreatic ductal adenocarcinoma (PDAC) cells compromises TGF-β-driven collective migration mediated by FAK and Rho/Rac signaling. Moreover, RNA-sequencing analyses highlight a TGF-β gene signature related to aggressiveness mediated by SMAD2 and 3 in the absence of SMAD4. Using PDAC patients cohorts, we reveal that SMAD4-negative tumors with high levels of (phospho)-SMAD2 are more aggressive and have a poorer prognosis. Thus, loss of SMAD4 tumor suppressive activity in PDAC is associated with oncogenic gain-of-function of SMAD2 and 3 and the onset of associated deleterious effects.
2022-10-09 | GSE178714 | GEO
Project description:SMAD4, a key mediator of TGF-beta signaling, plays a crucial role in T cells to prevent chronic intestinal inflammation through unknown mechanisms. We reveal that SMAD4 in CD8 T cells prevents chronic intestinal inflammation primarily in a TGF-beta-independent manner. Mechanistically, SMAD4, in CD8 T cells, acts as a basal and tonic repressor of TGF-beta-target genes at the transcriptional and epigenetic level, prior to any TGF-beta signal. SMAD4 deletion affects aberrantly a wide range of TGF-beta-target genes, thereby promoting accumulation and epithelial retention of CD8.alpha.beta T cells inversely to total TGF-beta signaling disruption. Moreover, SMAD4 deletion unleashes the expression of TGF-beta-signaling-repressors and hampers TGF-β-mediated CD8 T cell immunosuppression, eliciting their chronic activation. Hence, in a feedforward mechanism, SMAD4 both blocks the TGF-beta signature in CD8 T cells and pre-sensitizes them to TGF-beta.
2022-03-15 | GSE188933 | GEO
Project description:SMAD4, a key mediator of TGF-beta signaling, plays a crucial role in T cells to prevent chronic intestinal inflammation through unknown mechanisms. We reveal that SMAD4 in CD8 T cells prevents chronic intestinal inflammation primarily in a TGF-beta-independent manner. Mechanistically, SMAD4, in CD8 T cells, acts as a basal and tonic repressor of TGF-beta-target genes at the transcriptional and epigenetic level, prior to any TGF-beta signal. SMAD4 deletion affects aberrantly a wide range of TGF-beta-target genes, thereby promoting accumulation and epithelial retention of CD8.alpha.beta T cells inversely to total TGF-beta signaling disruption. Moreover, SMAD4 deletion unleashes the expression of TGF-beta-signaling-repressors and hampers TGF-β-mediated CD8 T cell immunosuppression, eliciting their chronic activation. Hence, in a feedforward mechanism, SMAD4 both blocks the TGF-beta signature in CD8 T cells and pre-sensitizes them to TGF-beta.
2022-03-15 | GSE188932 | GEO
Project description:Loss of TGF-beta growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-beta resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich protein (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers, such as Hepatocellular carcinoma (HCC). In this study, we identified SFPQ as a potent suppressor of TGF-beta signaling. The ability of SFPQ to suppress TGF-beta responses depended on its prion-like domain (PrLD) that drives phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy, and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of LLPS rendered cells hypersensitive to TGF-beta responses. Together, our data reveal a unique function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-beta tumor-suppressive activity.
2023-11-16 | GSE236125 | GEO
Project description:By performing oligonucleotide microarray analysis the role of Smad4 in response to TGF-ß was evaluated in established MDA-MB-468 Smad4 negative and positive clones that were treated with TGF-ß for different time points. Keywords: time-course
2006-04-25 | GSE2567 | GEO
Project description:Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. We identified a novel homozygous deletion of DACH1 in gliomas. We generated U87TR-Da glioma cell line, where DACH1 expression could be activated by exposure of cells to doxycycline, and examined changing global gene expression by DACH1 expression. Expression of DACH1 in U87TR-Da cells can be induced by exposure of the cells to doxycycline. We analyzed gene expression profiles of DACH1-induced/repressed U87TR-Da cells. And we also compared gene expression profiles of DACH1-induced/repressed U87TR-Da cells under different culture condition, DMEMF(serum-containing) and NBE(serum-free)
2011-07-19 | E-GEOD-19678 | biostudies-arrayexpress
Project description:Identification of novel TGF-b1 and BMP-7-regulated genes in epithelial cells.<br> <br> Human mammary epithelial cell line MDA-MB-468 that is lacking endogenous Smad4 was infected with either an adenovirus carrying GFP cDNA (control) or Smad4 cDNA (to restore the Smad4 activity in the cells). Cells were treated with TGF-b1 (0.5 ng/ml) or BMP-7 (300 ng/ml) for 2 or 12h. Smad4-independent vs Smad4-dependent response was measured. Also response to both growth factors was compared.
2004-03-15 | E-MEXP-78 | biostudies-arrayexpress