Transcriptional targets of Hippo signaling in mammalian cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE49384 | GEO | 2013/12/31
SECONDARY ACCESSION(S): PRJNA213852
REPOSITORIES: GEO
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Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway. Three mammalian cell lines (HEK293T, HepG2, HaCaT) were transfected with scramble siRNA controls or siRNAs against NF2 and LATS2, two core components of the Hippo pathway, simultaneously. Total RNAs were harvested four days after transfection to reveal the gene expression pattern unsing microarry. YAP and TAZ siRNAs were also transfected along with NF2 and LATS2 siRNAs to identify YAP/TAZ-dependent transcriptional targets upon loss of NF2/LATS2.
2013-12-31 | E-GEOD-49384 | biostudies-arrayexpress
Project description:The Hippo pathway plays a key role in development, organ size control, and tissue homeostasis, and its dysregulation contributes to cancer. The LATS tumor suppressor kinases phosphorylate and inhibit the YAP/TAZ transcriptional co-activators to suppress gene expression and cell growth. Through a screen of marine natural products, we identified microcolin B (MCB) as a Hippo activator. Structure-activity optimization yielded more potent MCB analogs, which led to identification of PITP as the direct molecular targets. We established a critical role of PITP in regulating LATS and YAP. Moreover, we showed that PITP influences the Hippo pathway via cellular PI4P. This study uncovers a previously unrecognized role of PITP in Hippo pathway regulation and as potential cancer therapeutic targets.
2022-03-20 | GSE198890 | GEO
Project description:The Hippo pathway is crucial in organ size control and tumorigenesis. The dys-regulation of Hippo/YAP axis is vastly observed in gastric cancer, while the effective therapeutic targets for Hippo/YAP axis are still not clear. It is important and urgent to identify reliable drug targets and the underlying mechanisms, which could inhibit the activity of Hippo/YAP axis and gastric cancer progression. In our current study, we demonstrate the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator for Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004-1239 could block the tumorigenesis in gastric cancer. Molecular studies reveal that the activation of CXCR7 could dephosphorylate YAP, facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gαq/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assay shows that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates CXCR7 is both the upstream signaling and downstream target for Hippo/YAP axis in gastric cancer. In general, we identified a novel positive feedback loop between CXCR7 and Hippo/YAP axis, while blockade of CXCR7 could be a plausible strategy for gastric cancer.
2023-11-15 | GSE233094 | GEO
Project description:The Hippo pathway downstream effectors, Yap and Taz, play key roles in cell proliferation and tissue growth, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed gene expression changes driven by Taz and compared these to Yap mediated changes to the transcriptome by measurement of gene expression on Affymetrix microarrays. To interrogate overlapping and unique transcriptional changes driven by these Hippo effectors, satellite cell-derived myoblasts were transduced with constitutively active TAZ S89A or YAP S127A retrovirus for 24h or 48h, with empty retrovirus as control. Triplicate microarray analyses of empty vector controls, hYAP1 S127A and TAZ S89A transgenic primary myoblasts were conducted.
2017-06-20 | E-MTAB-5395 | biostudies-arrayexpress
Project description:Splicing dysregulations extensively occur in cancers, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo-YAP signaling, a key pathway that regulates cell proliferation and organ size, is under control of a new splicing switch. We show that TEAD4, the transcription factor that mediates Hippo-YAP signaling, undergoes alternative splicing facilitated by the tumor suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks N-terminal DNA-binding domain but maintains YAP-interaction domain. TEAD4-S is located in both nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumor growth in xenograft mouse model. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether these data reveal a novel RBM4-mediated splicing switch that serves to fine-tune Hippo-YAP pathway. Cell lines stably expressing YAP, YAP/TEAD4-S, YAP/TEAD4-FL, YAP/RBM4 and control vector were created, and the total RNA was purified from the cells using TRIzol reagents. The polyadenylated RNAs were purified for construction of sequencing library using kapa TruSeq Total RNA Sample Prep kits (UNC High Throughput Sequencing Facility).
2016-06-16 | E-GEOD-80372 | biostudies-arrayexpress
Project description:Background—YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD sequence specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. Methods and Results—To identify genes directly regulated by YAP in cardiomyocytes, we combined differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. We validated YAP and TEAD occupancy of a conserved enhancer within the first intron of Pik3cb, and show that this enhancer drives YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the PI3K-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened the YAP mitogenic activity. Reciprocally, Yap loss-of-function impaired heart function and reduced cardiomyocyte proliferation and survival, all of which were significantly rescued by AAV-mediated Pik3cb expression. Conclusion—Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKT pathway and regulates cardiomyocyte proliferation and survival. Yap wild type ChIPseq and input
2015-02-20 | E-GEOD-57717 | biostudies-arrayexpress
Project description:The Hippo pathway plays an important role in regulating tissue homeostasis, and its effectors YAP and TAZ are responsible for mediating the vast majority of its physiological functions. Although YAP and TAZ are thought to be largely redundant and similarly regulated by Hippo signaling, they have developmental, structural, and physiological differences which suggest there may be differences in their regulation and downstream functions. To better understand the functions of YAP and TAZ in the Hippo pathway, we generated knockout cells and evaluated them in response to many conditions and stimuli. Here, we used RNA-seq to identify and compare differences in the transcriptional profiles between the YAP and TAZ.
2018-05-25 | GSE111583 | GEO
Project description:Background—YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD sequence specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. Methods and Results—To identify genes directly regulated by YAP in cardiomyocytes, we combined differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. We validated YAP and TEAD occupancy of a conserved enhancer within the first intron of Pik3cb, and show that this enhancer drives YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the PI3K-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened the YAP mitogenic activity. Reciprocally, Yap loss-of-function impaired heart function and reduced cardiomyocyte proliferation and survival, all of which were significantly rescued by AAV-mediated Pik3cb expression. Conclusion—Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKT pathway and regulates cardiomyocyte proliferation and survival. Two groups were involved in this study:TNTcreYapfl_het group and TNTcreYapfl_KO group. Each group contained three biological replicates. Embryo hearts were collected at E12.5 and dissociated. Cardiomyocytes were collected by FACS. The total RNA of cardiomyocytes were isolated for microarray analysis.
2015-02-20 | E-GEOD-57718 | 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 | GSE222960 | 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 | GSE222962 | GEO