Rattus norvegicus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA967199 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24698000_1.fastq.gz | Fastqsanger.gz | |||
| SRR24698000_2.fastq.gz | Fastqsanger.gz | |||
| SRR24698001_1.fastq.gz | Fastqsanger.gz | |||
| SRR24698001_2.fastq.gz | Fastqsanger.gz | |||
| SRR24698002_1.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptional coactivators of YAP/TAZ play key roles in cancers through transcriptional outputs. However, the mechanisms of their transactivation remain unclear, and effective and safe targeting solutions are lacking. Here, we discovered that YAP/ TAZ possess a hydrophobic transactivation domain (TAD). Knockout of TADs prevents tumor establishment due to growth defects and enhanced immune attack. TADs facilitate preinitiation complex (PIC) assembly by promoting TFIID recruitment in a TAF4-dependent manner and enhance RNA polymerase II (Pol II) elongation through MED15-dependent mediator complex recruitment. The bindings of TAD to the surface hydrophobic groove of MED15 induce its folding of the helix and hydrophobic interactions of TAD-MED15 boosts YAP-MED15 co-condensations thereby enhancing transcriptional hub formation and the expression of an oncogenic and immune suppressive transcriptional program. Synthesized small peptide TJ-M11 selectively disrupts the interactions of TADs with MED15 and TAF4, thereby suppressing tumor growth and sensitizing immunotherapy. This study indicates TADs of YAP/TAZ exhibit dual functions in PIC assembly and Pol II elongation, relying on hydrophobic interactions.
2025-04-02 | PXD060955 | Pride
Project description:In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells. ChIP-Seq experiments for MYC-HA (HA-IP) performed in IMEC primary breast epithelial cells. Input-samples were sequenced as controlls.
2015-10-28 | E-GEOD-66252 | biostudies-arrayexpress
Project description:Hippo effectors YAP/TAZ act as on-off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described so far through a hierarchical model in which elements of Hippo pathway are under the control of Focal Adhesions (FAs). Here we unveiled the molecular mechanism by which cell spreading and RhoA GTPase control FA formation through YAP to stabilize the anchorage of actin cytoskeleton to cell membrane. This mechanism required YAP co-transcriptional function and involved the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity led to the modification of cell mechanics, force development, adhesion strength, determined cell shaping, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify Hippo effector as the key determinant of cell mechanics in response to ECM cues.
2017-05-17 | E-MTAB-5217 | biostudies-arrayexpress
Project description:Biophysical features of the microenvironment such as stiffness of extracellular matrix (ECM), nanotopography, and biomechanical force are critical regulators of cellular potential and behavior, yet the effects of extrinsic mechanical cues on tumor cells remain poorly understood. Here we demonstrate that frictional force, or wall shear stress (WSS), caused by fluid flow supports invasive behavior in cancer cells through activation of negative effectors of the Hippo tumor suppressor pathway, YAP and TAZ. In biomimetic models of lymphatic vasculature, WSS stimulated motility. These effects were accompanied by YAP dephosphorylation at ser-127, YAP and TAZ nuclear localization, and transactivation of YAP/TAZ downstream targets, including CTGF, AMOTL2, and ANKRD1. YAP, but not TAZ, was strictly required for WSS-enhanced motility, as knockdown of YAP or blockade of YAP-TEAD interactions by a small molecule inhibitor, verteporfin, reduced cellular velocity to levels observed in static controls. YAP-mediated effects on motility were dependent upon Rho-associated kinase (ROCK) and LIM-domain kinase (LIMK), as pharmacological inhibition of their activity led to activation of the actin-severing protein cofilin and blocked YAP dephosphorylation by WSS, thereby impairing migration. These data provide a signaling mechanism whereby biomechanical forces may influence cancer cell metastasis and implicate YAP as a core component of mechanosensitive machinery that modulates cancer progression.
2017-03-08 | GSE73284 | GEO
Project description:The goal of this study was to identify YAP/TAZ direct transcriptional targets and transcriptional partners, through ChIP-sequencing and gene expression profiling. ChIP-seq analysis of YAP, TAZ, TEAD4 and JUN in MDA-MB-231 cells. Two independent replicates were analysed for each TF, as well as for negative controls.
2015-08-03 | E-GEOD-66081 | biostudies-arrayexpress
Project description:The optic vesicle comprises a pool of bi-potential progenitor cells from which the retinal pigment epithelium (RPE) and neural retina fates segregate during ocular morphogenesis. Several transcription factors and signaling pathways have been shown to be important for RPE maintenance and differentiation, but an understanding of the initial fate specification and determination of this ocular cell type is lacking. We show that Yap/Taz-Tead activity is necessary and sufficient for optic vesicle progenitors to adopt RPE identity in zebrafish. A Teadresponsive transgene is expressed within the domain of the optic cup from which RPE arises, and Yap immunoreactivity localizes to the nuclei of prospective RPE cells. yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma. Loss of RPE in yap mutants is exacerbated in combination with taz (wwtr1) mutant alleles such that, when Yap and Taz are both absent, optic vesicle progenitor cells completely lose their ability to form RPE. The mechanism of Yap dependent RPE cell type determination is reliant on both nuclear localization of Yap and interaction with a Tead co-factor. In contrast to loss of Yap and Taz, overexpression of either protein within optic vesicle progenitors leads to ectopic pigmentation in a dosagedependent manner. Overall, this study identifies Yap and Taz as key early regulators of RPE genesis and provides a mechanistic framework for understanding the congenital ocular defects of Sveinsson’s chorioretinal atrophy and congenital retinal coloboma. 60 pooled eyes from 36 hpf wild type or vsx2:Gal4/dsRed:14xUAS:YapS87A embryos were pooled for one sample. Three wild type and three vsx2:Gal4/dsRed:14xUAS:YapS87A pools were analyzed for RNA.
2015-08-06 | E-GEOD-71681 | biostudies-arrayexpress
Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.
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