Transcriptional profiles of Tead1/4 Knockout and Unedited CT26 Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236855 | GEO | 2024/12/31
REPOSITORIES: GEO
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Project description:The vestigial like family proteins (VGLL) are thought to regulate transcription by interacting with the TEA domain transcription factors (TEAD), the primary mediators of the Hippo pathway. However, the functional regulation of VGLL proteins remains poorly characterized. Here, we explored the molecular mechanism of two VGLL2 and TEAD1 fusion proteins generated by recurrent translocations in spindle cell rhabdomyosarcoma. We demonstrated that, compared to VGLL2 and TEAD1 alone, VGLL2-NCOA2 and TEAD1-NCOA2 act as strong transcriptional activators of TEAD-mediated transcription. Although VGLL2-NCOA2 and Yes1 associated transcriptional regulator (YAP) control overlapping transcriptional programs and chromatin landscapes, the downstream transcription induced by the fusion proteins does not require YAP and WW domain containing transcription regulator 1 (TAZ). Furthermore, VGLL2-NCOA2 and TEAD1-NCOA2 fusions engage distinct epigenetic regulation by recruiting E1A binding protein p300 (p300) to drive TEAD-dependent transcription. We showed that small molecule p300 inhibition can suppress VGLL2-NCOA2 and TEAD1-NCOA2-induced oncogenic transformation both in vitro and in vivo. Overall, our data reveal a tumorigenic mechanism of VGLL and TEAD fusion proteins that is related to the Hippo pathway but independent of YAP/TAZ, suggesting potential therapeutic strategies for tumors carrying VGLL, TEAD, or nuclear receptor coactivator (NCOA) gene rearrangements.
2024-05-22 | GSE260782 | GEO
Project description:The vestigial like family proteins (VGLL) are thought to regulate transcription by interacting with the TEA domain transcription factors (TEAD), the primary mediators of the Hippo pathway. However, the functional regulation of VGLL proteins remains poorly characterized. Here, we explored the molecular mechanism of two VGLL2 and TEAD1 fusion proteins generated by recurrent translocations in spindle cell rhabdomyosarcoma. We demonstrated that, compared to VGLL2 and TEAD1 alone, VGLL2-NCOA2 and TEAD1-NCOA2 act as strong transcriptional activators of TEAD-mediated transcription. Although VGLL2-NCOA2 and Yes1 associated transcriptional regulator (YAP) control overlapping transcriptional programs and chromatin landscapes, the downstream transcription induced by the fusion proteins does not require YAP and WW domain containing transcription regulator 1 (TAZ). Furthermore, VGLL2-NCOA2 and TEAD1-NCOA2 fusions engage distinct epigenetic regulation by recruiting E1A binding protein p300 (p300) to drive TEAD-dependent transcription. We showed that small molecule p300 inhibition can suppress VGLL2-NCOA2 and TEAD1-NCOA2-induced oncogenic transformation both in vitro and in vivo. Overall, our data reveal a tumorigenic mechanism of VGLL and TEAD fusion proteins that is related to the Hippo pathway but independent of YAP/TAZ, suggesting potential therapeutic strategies for tumors carrying VGLL, TEAD, or nuclear receptor coactivator (NCOA) gene rearrangements.
2024-05-22 | GSE260783 | GEO
Project description:Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are dictated by YAP/TAZ-TEAD – a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2, and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fueling nutrient mTORC1 signaling. By orchestrating the transcription of a repertoire of cell-surface transporters, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 pathway activation. Dissociating mTORC1 from these nutrient inputs – elicited by the loss of Rag GTPases – inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. These findings define a pivotal role for YAP/TAZ-TEAD in steering endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
2022-05-08 | PXD026872 | Pride
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.
2014-04-02 | E-GEOD-56445 | biostudies-arrayexpress
Project description:The vestigial like family proteins (VGLL) are thought to regulate transcription by interacting with the TEA domain transcription factors (TEAD), the primary mediators of the Hippo pathway. However, the functional regulation of VGLL proteins remains poorly characterized. Here, we explored the molecular mechanism of two VGLL2 and TEAD1 fusion proteins generated by recurrent translocations in spindle cell rhabdomyosarcoma. We demonstrated that, compared to VGLL2 and TEAD1 alone, VGLL2-NCOA2 and TEAD1-NCOA2 act as strong transcriptional activators of TEAD-mediated transcription. Although VGLL2-NCOA2 and Yes1 associated transcriptional regulator (YAP) control overlapping transcriptional programs and chromatin landscapes, the downstream transcription induced by the fusion proteins does not require YAP and WW domain containing transcription regulator 1 (TAZ). Furthermore, VGLL2-NCOA2 and TEAD1-NCOA2 fusions engage distinct epigenetic regulation by recruiting E1A binding protein p300 (p300) to drive TEAD-dependent transcription. We showed that small molecule p300 inhibition can suppress VGLL2-NCOA2 and TEAD1-NCOA2-induced oncogenic transformation both in vitro and in vivo. Overall, our data reveal a tumorigenic mechanism of VGLL and TEAD fusion proteins that is related to the Hippo pathway but independent of YAP/TAZ, suggesting potential therapeutic strategies for tumors carrying VGLL, TEAD, or nuclear receptor coactivator (NCOA) gene rearrangements.
2024-05-22 | GSE260781 | GEO
Project description:Regulation of organ size is important for development and tissue homeostasis. In Drosophila, Hippo signaling controls organ size by regulating the activity of a TEAD transcription factor, Scalloped, through modulation of its coactivator protein Yki. The role of mammalian Tead proteins in growth regulation, however, remains unknown. Here we examined the role of mouse Tead proteins in growth regulation. In NIH3T3 cells, cell density and Hippo signaling regulated the activity of Tead proteins by modulating nuclear localization of a Yki homologue, Yap, and the resulting change in Tead activity altered cell proliferation. Tead2-VP16 mimicked Yap overexpression, including increased cell proliferation, reduced cell death, promotion of EMT, lack of cell contact inhibition, and promotion of tumor formation. Growth promoting activities of various Yap mutants correlated with their Tead-coactivator activities. Tead2-VP16 and Yap regulated largely overlapping sets of genes. However, only a few of the Tead/Yapregulated genes in NIH3T3 cells were affected in Tead1-/-;Tead2-/- or Yap-/- embryos. Most of the previously identified Yap-regulated genes were not affected in NIH3T3 cells or mutant mice. In embryos, levels of nuclear Yap and Tead1 varied depending on cell types. Strong nuclear accumulation of Yap and Tead1 were seen in myocardium, correlating with requirements of Tead1 for proliferation. However, their distribution did not always correlate with proliferation. Taken together, mammalian Tead proteins regulate cell proliferation and contact inhibition as a transcriptional mediator of Hippo signaling, but the mechanisms by which Tead/Yap regulate cell proliferation differ depending on cell types, and Tead, Yap and Hippo signaling may play multiple roles in mouse embryos. We used microarrays to know the gene expression profiles regurated by Tead2-VP16, Tead2-EnR, Yap, and cell density in NIH3T3 cells. Keywords: Cell density, genetic modification Tead2-VP16-, Tead2-EnR-, Yap- and control vector-expressing cells were cultured at low or high density for RNA extraction and hybridization on Affymetrix microarrays.
2008-11-20 | E-GEOD-12498 | biostudies-arrayexpress
Project description:The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their partner transcription factors, the TEAD1-4 factors, are therefore promising anti-cancer targets. Due to frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and Lats2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in human subcutaneous xenograft models and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the exquisite sensitivity of mesothelioma to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has great potential to treat multiple Hippo-mutant solid tumor types.
2023-10-04 | GSE222962 | GEO
Project description:The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their partner transcription factors, the TEAD1-4 factors, are therefore promising anti-cancer targets. Due to frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and Lats2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in human subcutaneous xenograft models and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the exquisite sensitivity of mesothelioma to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has great potential to treat multiple Hippo-mutant solid tumor types.
2023-10-04 | GSE222960 | GEO
Project description:Proper lung function relies on precisely balanced numbers of specialized epithelial cell types that work together and are maintained in homeostasis. In this study we have described essential roles for the transcriptional regulators YAP and TAZ, which are key effectors of Hippo pathway signaling, in maintaining lung epithelial homeostasis. Phenotypes associated with Yap/Taz deletion include alveolar defects and a striking development of goblet cell metaplasia throughout the airways. Knockdown of YAP and TAZ in HBECs similarly drives mucin expression. The TEAD family of transcription factors are well characterized partners of the YAP/TAZ transcriptional effectors, and we have found that knockdown of TEAD1-4 similarly drives elevated mucin expression. In order to further understand the role of the TEAD transcription factors in human lung epithelial cell fate, we conducted TEAD Chromatin Immunopreciptitation (ChIP)-Sequencing.
2021-08-19 | GSE158306 | GEO
Project description:Proper lung function relies on precisely balanced numbers of specialized epithelial cell types that work together and are maintained in homeostasis. In this study we have described essential roles for the transcriptional regulators YAP and TAZ, which are key effectors of Hippo pathway signaling, in maintaining lung epithelial homeostasis. Phenotypes associated with Yap/Taz deletion include alveolar defects and a striking development of goblet cell metaplasia throughout the airways. Knockdown of YAP and TAZ in HBECs similarly drives mucin expression. The TEAD family of transcription factors are well characterized partners of the YAP/TAZ transcriptional effectors, and we have found that knockdown of TEAD1-4 similarly drives elevated mucin expression. In order to further understand the role of the TEAD transcription factors in human lung epithelial cell fate, we conducted TEAD Chromatin Immunopreciptitation (ChIP)-Sequencing.
2021-08-19 | GSE158305 | GEO