Inducible smooth muscle specific deletion of Yap1/Wwtr1 in mouse [Thoracic aorta RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE180631 | GEO | 2022/02/09
REPOSITORIES: GEO
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Project description:YAP and TAZ are transcriptional co-activators and downstream effectors of the Hippo pathway, which play crucial roles in organ size control and cancer pathogenesis. Genetic deletion of YAP/TAZ has revealed their critical importance for embryonic development of the heart, vasculature and gastrointestinal mesenchyme. The aim of this study was to determine the functional role of YAP/TAZ in adult smooth muscle cell in vivo.
2020-10-28 | GSE150603 | GEO
Project description:YAP and TAZ are transcriptional co-activators and downstream effectors of the Hippo pathway, which play crucial roles in organ size control and cancer pathogenesis. Genetic deletion of YAP/TAZ has revealed their critical importance for embryonic development of the heart, vasculature and gastrointestinal mesenchyme. The aim of this study was to determine the long term role of YAP/TAZ in adult vascular smooth muscle in vivo. We used the novel Itga8-CreERT2 mouse for deletion of YAP/TAZ (i8-Y/T-KO).
2023-08-13 | GSE240233 | GEO
Project description:TAZ, also known as WWTR1, is the one of the effectors of Hippo pathway. With its paralog, YAP, TAZ promotes organ size growth as well as tumor metastasis. In human renal carcinoma cells, we found that TAZ-silencing induces resisntance toward erastin-induced ferroptosis. In this study, TAZ is silencing in clear cell carcinoma cell line RCC4 to elucidate the downstream targets that promotes the resistance toward erastin-induced ferroptosis.
2019-09-03 | GSE121689 | 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:The Hippo pathway plays a crucial in organ size control during development and tissue homeostasis in adult life. To examine a role for Hippo signaling in the intestinal epithelium, we analyzed gene expression patterns in the mouse intestinal epithelilum transfected with siRNAs or expression plasmids for shRNAs targeting the Hippo pathway effectors, YAP and TAZ. We performed two independent series of experiments (siGFP (n=3) vs siYAP/siTAZ (n=3), and shLacZ (n=1) vs shYAP/shTAZ (n=1)). Control siRNA (siGFP), YAP/TAZ siRNAs, or expression plasmids for control shRNA (shLacZ) or YAP/TAZ shRNAs were introduced into the mouse intestinal epithelium by the newly-developed in vivo transfection method. Four days after transfection, intestinal epithelial cells were isolated from the tissues and total RNA was extracted.
2014-07-18 | E-GEOD-45155 | biostudies-arrayexpress
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:Aims: Hippo signalling is an evolutionarily conserved pathway that controls organ size by regulating apoptosis, cell proliferation and stem cell self-renewal. Recently, the pathway has been shown to exert powerful growth regulatory activity in cardiomyocytes. However, the functional role of this stress- and cell death-related pathway in the human heart and cardiomyocytes is not known. In this study, we investigated the role of the transcriptional co-activators of Hippo signalling, YAP and TAZ, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in response to cardiotoxic agents and investigated the effects of modulating the pathway on cardiomyocyte function and survival. Methods and Results: RNA sequencing analysis of human heart samples with doxorubicin-induced end-stage heart failure and healthy controls showed YAP and ERBB2 (HER2) as upstream regulators of differentially expressed genes correlated with doxorubicin treatment. Thus, we tested the effects of doxorubicin and/or small molecule inhibitor lapatinib on hiPSC-CM in vitro . Using an automated high contentscreen of 96 clinically relevant chemotherapeutic drugs, we showed that doxorubicin induced the highest activation of YAP/TAZ nuclear translocation in both hiPSC-CM and control MCF7 breast cancer cells. The overexpression of YAP rescued doxorubicin- induced cell loss in hiPSC-CM by inhibiting apoptosis and inducing proliferation. In contrast, silencing of YAP and TAZ by siRNAs resulted in elevated mitochondrial membrane potential loss in response to doxorubicin. Human iPSC-CM calcium transients did not change in response to YAP/TAZ silencing. Conclusions: Our results suggest that Hippo signalling is involved in clinical anthracycline-induced cardiomyopathy. Modelling with hiPSC-CM in vitro showed similar responses to doxorubicin as adult cardiomyocytes and revealed a potential cardioprotective effect of YAP in doxorubicin-induced cardiotoxicity.
2022-01-21 | GSE193861 | GEO
Project description:Human cancer is often caused by dysfunctional developmental pathways, but such mechanisms do not always present clear opportunities for therapeutic intervention. This is exemplified by the Hippo tumor suppressor pathway, which is comprised of a kinase module that restrains the function of YAP/TAZ transcriptional coactivators; a pathway that becomes dysregulated in a wide array of human cancers. Hence, YAP/TAZ hyperactivation is a tumorigenic mechanism and a validated therapeutic target in oncology. In this study, we used a paralog co-targeting genetic screening strategy to identify the kinases MARK2/3 as co-dependencies of YAP/TAZ in diverse cancer contexts. We use biochemical and epistasis experiments to show that MARK2/3 phosphorylate and inhibit the activity of Hippo pathway components NF2, MST1/2, and MAP4Ks, which leads to indirect upstream control of LATS1/2 activity. In addition, MARK2/3 directly phosphorylate YAP/TAZ to shield these coactivators from LATS1/2-mediated inhibition. The net consequence of this multi-level regulation is that YAP/TAZ-dependent human cancers have an absolute requirement for MARK2/3 catalytic activity to sustain tumor cell proliferation and viability. To simulate therapeutic targeting of MARK2/3 in vivo, we adapted the EPIYA-repeat region of the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts potent anti-tumor activity via on-target mechanisms. Together, these findings reveal MARK2/3 as an obligate catalytic requirement for YAP/TAZ function in human cancer; kinase targets that may allow for novel pharmacology that restores Hippo-mediated tumor suppression.
2024-07-25 | PXD054192 | Pride
Project description:Human cancer is often caused by dysfunctional developmental pathways, but such mechanisms do not always present clear opportunities for therapeutic intervention. This is exemplified by the Hippo tumor suppressor pathway, which is comprised of a kinase module that restrains the function of YAP/TAZ transcriptional coactivators; a pathway that becomes dysregulated in a wide array of human cancers. Hence, YAP/TAZ hyperactivation is a tumorigenic mechanism and a validated therapeutic target in oncology. In this study, we used a paralog co-targeting genetic screening strategy to identify the kinases MARK2/3 as co-dependencies of YAP/TAZ in diverse cancer contexts. We use biochemical and epistasis experiments to show that MARK2/3 phosphorylate and inhibit the activity of Hippo pathway components NF2, MST1/2, and MAP4Ks, which leads to indirect upstream control of LATS1/2 activity. In addition, MARK2/3 directly phosphorylate YAP/TAZ to shield these coactivators from LATS1/2-mediated inhibition. The net consequence of this multi-level regulation is that YAP/TAZ-dependent human cancers have an absolute requirement for MARK2/3 catalytic activity to sustain tumor cell proliferation and viability. To simulate therapeutic targeting of MARK2/3 in vivo, we adapted the EPIYA-repeat region of the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts potent anti-tumor activity via on-target mechanisms. Together, these findings reveal MARK2/3 as an obligate catalytic requirement for YAP/TAZ function in human cancer; kinase targets that may allow for novel pharmacology that restores Hippo-mediated tumor suppression.
2024-07-25 | PXD044829 | Pride
Project description:Abstract Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed Taz in vivo and ex vivo in comparison to Yap. Taz was expressed in activated satellite cells. siRNA knockdown or constitutive expression of wildtype or constitutively active TAZ mutants showed that TAZ promoted proliferation, a function that was shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene symbol Wwtr1-/-) knockout mice, there were no overt effect on regeneration. However, conditional knockout of Yap in satellite cells of Pax7Cre-ERT2/+ : Yapflox/flox : Rosa26Lacz mice produced a marked regeneration deficit. To identify potential mechanisms, microarray analysis showed many common Taz/Yap targets, but Taz also regulates some genes independently of Yap, including myogenic genes such as Pax7, Myf5 and Myod1. Proteomic analysis of Yap/Taz revealed many common binding partners, but Taz also interacts with proteins distinct from Yap, that are mainly involved in myogenesis and aspects of cytoskeleton organization. Neither TAZ nor YAP bind members of the Wnt destruction complex but both extensively changed expression of Wnt and Wnt-cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to promote myogenic differentiation.
2017-06-13 | PXD005751 | Pride