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Ena-DATASET-CRUK-CI-11-11-2015-14:57:45:115-9 - samples

ABSTRACT: Data from the paper Context-specific Effects of TGFβ/SMAD3 in Cancer Are Modulated by the Epigenome. Tufegdzic et al, Cell Reports 2015

PROVIDER: EGAD00001001667 | EGA |

REPOSITORIES: EGA

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Context-Specific Effects of TGF-β/SMAD3 in Cancer Are Modulated by the Epigenome.

Tufegdzic Vidakovic Ana A Rueda Oscar M OM Vervoort Stephin J SJ Sati Batra Ankita A Goldgraben Mae Akilina MA Uribe-Lewis Santiago S Greenwood Wendy W Coffer Paul J PJ Bruna Alejandra A Caldas Carlos C

Cell reports 20151210 11

The transforming growth factor beta (TGF-β) signaling pathway exerts opposing effects on cancer cells, acting as either a tumor promoter or a tumor suppressor. Here, we show that these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGF-β signaling, and the distinct epigenomes of breast-tumor-initiating cells (BTICs). These effects of TGF-β are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC ...[more]

PMID: 26686634

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ena-DATASET-CRUK-CI-11-11-2015-15:29:28:770-13 - samples

Project description:Data from the paper Context-specific Effects of TGFβ/SMAD3 in Cancer Are Modulated by the Epigenome. Tufegdzic et al, Cell Reports 2015

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Project description:Data from the paper Context-specific Effects of TGFβ/SMAD3 in Cancer Are Modulated by the Epigenome. Tufegdzic et al, Cell Reports 2015

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Smad2 and Smad3 have differential sensitivity in relaying TGF b signaling and inversely regulate early lineage specification

Project description:The transforming growth factor beta (TGFβ) related signaling is one of the most important signaling pathways regulating early developmental events. Smad2 and Smad3 are structurally similar and it is mostly considered that they are equally important in mediating TGFβ signals. Here, we show that Smad3 is an insensitive TGFβ transducer as compared with Smad2. Smad3 preferentially localizes within the nucleus and is thus sequestered from membrane signaling. The ability of Smad3 in oligomerization with Smad4 upon agonist stimulation is also impaired given its unique linker region. Smad2 mediated TGFβ signaling plays a crucial role in epiblast development and patterning of three germ layers. However, signaling unrelated nuclear localized Smad3 is dispensable for TGFβ signaling-mediated epiblast specification, but important for early neural development, an event blocked by TGFβ/Smad2 signaling. Both Smad2 and Smad3 bind to the conserved Smads binding element (SBE), but they show nonoverlapped target gene binding specificity. We conclude that Smad2 and Smad3 possess differential sensitivities in relaying TGFβ signaling and have distinct roles in regulating early developmental events.

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Characterization of RSK3 interactome in human cells

Project description:Cellular senescence is characterized by a proliferation arrest accompanied by a senescence-associated secretory phenotype (SASP) in normal epithelial cells. During carcinogenesis cells lose the ability to undergo senescence, at least the associated proliferation arrest, in response to stresses such as oncogenes, or TGFβ, a SASP molecule able to mediate autocrine and paracrine senescence. A genetic screen in human mammary epithelial cells (HMECs) identified that the serine threonine kinase RSK3 reverts TGFβ-induced senescence. Interestingly, RSK3 expression decreases in response to TGFβ in a SMAD3-dependent manner, and its constitutive expression rescues SMAD3-induced premature senescence, indicating that decrease of RSK3 itself contributes to TGFβ-induced senescence. Mechanistically, RSK3 regulates senescence by inhibiting NF-κΒ pathway through the decrease in proteasome-mediated IκBα degradation. To better understand how RSK3 might interfere with IκBα degradation, we conducted immunoprecipitation experiments to purify the RSK3-Flag protein and its partners. Mass spectrometry-based proteomics was then performed to identify potential partners.

2023-11-27 | PXD045450 | Pride

Data from the paper Context-specific Effects of TGFβ/SMAD3 in Cancer Are Modulated by the Epigenome. Tufegdzic et al, Cell Reports 2015

Project description:The transforming growth factor beta (TGFβ) signalling pathway exerts opposing effects on cancer cells, acting either as a tumor-promoter or as a tumor-suppressor. Here we show these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGFβ signalling, and the distinct epigenomes of breast tumor initiating cells (BTICs). These effects of TGFβ are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC- suppressing contexts. Our data show cell type-specific epigenetic configurations provide a modulatory layer by determining accessibility of genes to regulation by TGFβ/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status, and is crucial for TGFβ-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGFβ in cancer.

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Project description:TGFβ activates a signal transduction cascade that results in the transcription of genes, primarily through the DNA-binding transcription factor SMAD3. The objective of this study is to identify SMAD3 binding targets and the molecular pathways affected by the TGFβ1/SMAD3 signal transduction on a genome-wide scale.

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JMJD3 is needed to regulate TGF beta responsive genes.

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Genome wide binding sites of Smad3 and JMJD3 in neural stem cells

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H522 lung cancer cells' TGFbeta response was restored by putting back BRG1 and TGFbRII

Project description:The transcription factors Smad2 and Smad3 mediate a large set of genes responses induced by the cytokine TGFβ, but the extent to which their function depends on chromatin remodeling remains to be defined. We observed interactions between these two Smads and BRG1, BAF250b, BAF170 and BAF155, which are core components of the SWI/SNF chromatin-remodeling complex. Smad2 and Smad3 have a similar affinity for these components in vitro, and their interactions are primarily mediated by BRG1. In vivo, however, BRG1 predominantly interacts with Smad3, and this interaction is enhanced by TGFβ stimulation. Our results suggest that BRG1 is incorporated into transcriptional complexes that are formed by activated Smads in the nucleus, on target promoters. Using BRG1-deficient cell systems(H522 lung cancer cells), we defined the BRG1 dependence of the TGFβ transcriptional program genome-wide. Most TGFβ gene responses in human epithelial cells are dependent on BRG1 function. Remarkably, BRG1 is not required for the TGFβ-mediated induction of SMAD7 and SNON, which encode key mediators of negative feedback in this pathway. Our results provide a genome-wide scope of the participation of BRG1 in TGFβ action and suggest a widespread yet differential involvement of BRG1 SWI/SNF remodeler in the transcriptional response of many genes to this cytokine. Keywords: comparative genomic hybridization

2008-03-18 | GSE10847 | GEO

Genomic binding profiles for ZNF165, ZNF446, and SMAD3 in triple-negative breast cancer

Project description:The testis protein ZNF165 is aberrantly expressed in triple-negative breast cancer (TNBC), where it modulates TGFβ signaling to promote tumor growth and survival. To investigate whether ZNF165 functions in this capacity via cooperation with SMAD3, a canonical TGFβ-induced transcription factor, we performed ChIP-seq for both factors in TNBC cell lines (WHIM12 and SUM159). Additionally, we established genomic binding profiles for ZNF446, a previously uncharacterized transcription factor that we have identified as a member of a ZNF165-SMAD3 complex.

2020-06-10 | GSE130364 | GEO

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