Academic literature on the topic 'Transcriptional co-activator with PDZ-Binding motif (TAZ)'

Abstract Transcriptional co-activator with PDZ-binding motif (TAZ) is a key downstream effector of the Hippo tumor-suppressor pathway. The functions of TAZ in the kidney, especially in tubular epithelial cells, are not well-known. To elucidate the adaptive expression, protective effects on kidney injury, and signaling pathways of TAZ in response to acute kidney injury (AKI), we used in vitro (hypoxia-treated human renal proximal tubular epithelial cells [RPTECs]) and in vivo (mouse ischemia–reperfusion injury [IRI]) models of ischemic AKI. After ischemic AKI, TAZ was up-regulated in RPTECs and the renal cortex or tubules. Up-regulation of TAZ in RPTECs subjected to hypoxia was controlled by IκB kinase (IKK)/nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) signaling. TAZ overexpression attenuated hypoxic and oxidative injury, inhibited apoptosis and activation of p38 and c-Jun N-terminal kinase (JNK) proteins, and promoted wound healing in an RPTEC monolayer. However, TAZ knockdown aggravated hypoxic injury, apoptosis, and activation of p38 and JNK signaling, delayed wound closure of an RPTEC monolayer, and promoted G0/G1 phase cell-cycle arrest. Chloroquine and verteporfin treatment produced similar results to TAZ overexpression and knockdown in RPTECs, respectively. Compared with vehicle-treated mice, chloroquine treatment increased TAZ in the renal cortex and tubules, improved renal function, and attenuated tubular injury and tubular apoptosis after renal IRI, whereas TAZ siRNA and verteporfin decreased TAZ in the renal cortex and tubules, deteriorated renal failure and tubular injury, and aggravated tubular apoptosis. Our findings indicate the renoprotective role of tubular TAZ in ischemic AKI. Drugs augmenting (e.g., chloroquine) or suppressing (e.g., verteporfin) TAZ in the kidney might be beneficial or deleterious to patients with AKI.

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the primary downstream effectors of the Hippo signaling pathway. This pathway plays a crucial role in regulating organ size, maintaining tissue homeostasis, and controlling cellular processes such as fate determination and tissue development. This review provides an overview of the current understanding of how the transcriptional regulators YAP and TAZ contribute to the physiological and pathological processes in tissues and cells associated with the skeletal motor system. The underlying molecular mechanisms and mechanical transduction were reviewed.

The transcriptional co-activator with PDZ binding motif (TAZ) is a key effector of the Hippo signaling pathway. We and others previously reported that high expression levels of TAZ are positively associated with decreased survival rates and shorter times to relapse in basal-like breast cancer (BLBC) patients. The oncogenic activity of TAZ involves the regulation of diverse signal transduction pathways that direct processes such as cell proliferation, migration, and resistance to apoptosis, albeit through poorly characterized gene expression programs. Here, using a tet-inducible system in mammary epithelial MCF10A cells, we have characterized the TAZ-regulated transcription program using RNA sequencing in a temporal and spatial manner. We further identified global TAZ binding sites at different TAZ activation time points by chromatin immunoprecipitation (ChIP) sequencing analysis. We found that the vast majority of TAZ was rapidly localized in enhancer regions at the early TAZ activation time point and then gradually spread to promoter regions. TAZ bound to enhancer regions following a switch in potential TEAD and FOSL2 transcription factor motifs. Furthermore, the ATAC sequencing analysis indicated that TAZ activation led to chromatin structural alterations. Together, our results have revealed the landscape of genome-wide TAZ binding sites and may lead to improvements in the current understanding of how TAZ regulates the gene expression program that contributes to the development of breast cancer.

Despite recent efforts, prostate cancer (PCa) remains one of the most common cancers in men. Currently, there is no effective treatment for castration-resistant prostate cancer (CRPC). There is, therefore, an urgent need to identify new therapeutic targets. The Hippo pathway and its downstream effectors—the transcriptional co-activators, Yes-associated protein (YAP) and its paralog, transcriptional co-activator with PDZ-binding motif (TAZ)—are foremost regulators of stem cells and cancer biology. Defective Hippo pathway signaling and YAP/TAZ hyperactivation are common across various cancers. Here, we draw on insights learned from other types of cancers and review the latest advances linking the Hippo pathway and YAP/TAZ to PCa onset and progression. We examine the regulatory interaction between Hippo-YAP/TAZ and the androgen receptor (AR), as main regulators of PCa development, and how uncontrolled expression of YAP/TAZ drives castration resistance by inducing cellular stemness. Finally, we survey the potential therapeutic targeting of the Hippo pathway and YAP/TAZ to overcome PCa.

Helicobacter pylori infection, the main risk factor for gastric cancer (GC), leads to an epithelial–mesenchymal transition (EMT) of gastric epithelium contributing to gastric cancer stem cell (CSC) emergence. The Hippo pathway effectors yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) control cancer initiation and progression in many cancers including GC. Here, we investigated the role of TAZ in the early steps of H. pylori-mediated gastric carcinogenesis. TAZ implication in EMT, invasion, and CSC-related tumorigenic properties were evaluated in three gastric epithelial cell lines infected by H. pylori. We showed that H. pylori infection increased TAZ nuclear expression and transcriptional enhancer TEA domain (TEAD) transcription factors transcriptional activity. Nuclear TAZ and zinc finger E-box-binding homeobox 1 (ZEB1) were co-overexpressed in cells harboring a mesenchymal phenotype in vitro, and in areas of regenerative hyperplasia in gastric mucosa of H. pylori-infected patients and experimentally infected mice, as well as at the invasive front of gastric carcinoma. TAZ silencing reduced ZEB1 expression and EMT phenotype, and strongly inhibited invasion and tumorsphere formation induced by H. pylori. In conclusion, TAZ activation in response to H. pylori infection contributes to H. pylori-induced EMT, invasion, and CSC-like tumorigenic properties. TAZ overexpression in H. pylori-induced pre-neoplastic lesions and in GC could therefore constitute a biomarker of early transformation in gastric carcinogenesis.

Members of the highly related TEF-1 (transcriptional enhancer factor-1) family (also known as TEAD, for TEF-1, TEC1, ABAA domain) bind to MCAT (muscle C, A and T sites) and A/T-rich sites in promoters active in cardiac, skeletal and smooth muscle, placenta, and neural crest. TEF-1 activity is regulated by interactions with transcriptional co-factors [p160, TONDU (Vgl-1, Vestigial-like protein-1), Vgl-2 and YAP65 (Yes-associated protein 65 kDa)]. The strong transcriptional co-activator YAP65 interacts with all TEF-1 family members, and, since YAP65 is related to TAZ (transcriptional co-activator with PDZ-binding motif), we wanted to determine if TAZ also interacts with members of the TEF-1 family. In the present study, we show by GST (glutathione S-transferase) pull-down assays, by co-immunoprecipitation and by modified mammalian two-hybrid assays that TEF-1 interacts with TAZ in vitro and in vivo. Electrophoretic mobility-shift assays with purified TEF-1 and GST–TAZ fusion protein showed that TAZ interacts with TEF-1 bound to MCAT DNA. TAZ can interact with endogenous TEF-1 proteins, since exogenous TAZ activated MCAT-dependent reporter promoters. Like YAP65, TAZ interacted with all four TEF-1 family members. GST pull-down assays with increasing amounts of [35S]TEF-1 and [35S]RTEF-1 (related TEF-1) showed that TAZ interacts more efficiently with TEF-1 than with RTEF-1. This differential interaction also extended to the interaction of TEF-1 and RTEF-1 with TAZ in vivo, as assayed by a modified mammalian two-hybrid experiment. These data show that differential association of TEF-1 proteins with transcriptional co-activators may regulate the activity of TEF-1 family members.

Tissue fibrosis represents a complex pathological condition characterized by the excessive accumulation of collagenous extracellular matrix (ECM) components, resulting in impaired organ function. Fibroblasts are central to the fibrotic process and crucially involved in producing and depositing collagen-rich ECM. Apart from their primary function in ECM synthesis, fibroblasts engage in diverse activities such as inflammation and shaping the tissue microenvironment, which significantly influence cellular and tissue functions. This review explores the role of Yes-associated protein (Yap) and Transcriptional co-activator with PDZ-binding motif (Taz) in fibroblast signaling and their impact on tissue fibrosis. Gaining a comprehensive understanding of the intricate molecular mechanisms of Yap/Taz signaling in fibroblasts may reveal novel therapeutic targets for fibrotic diseases.

Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.

Enhanced Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling is correlated with the extraprostatic extension of prostate cancer. However, the mechanism by which YAP/TAZ signaling becomes hyperactive and drives prostate cancer progression is currently unclear. In this study, we revealed that higher expression of CCM1, which is uniquely found in advanced prostate cancer, is inversely correlated with metastasis-free and overall survival in patients with prostate cancer. We also demonstrated that CCM1 induces the metastasis of multiple types of prostate cancer cells by regulating YAP/TAZ signaling. Mechanistically, CCM1, a gene mutated in cerebral cavernous malformation, suppresses DDX5, which regulates the suppression of YAP/TAZ signaling, indicating that CCM1 and DDX5 are novel upstream regulators of YAP/TAZ signaling. Our findings highlight the importance of CCM1-DDX5-YAP/TAZ signaling in the metastasis of prostate cancer cells.

The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP–TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.

Biomedical Sciences
Ph.D.
The Hippo signaling pathway was first discovered in Drosophila melanogaster and is involved in organ size control by regulating cell proliferation and apoptosis. This well conserved pathway is activated by various signal inputs, including cell-cell contact, mechanotransduction, and G-protein coupled receptors, with signals converging on the downstream effector protein Yap and its homologue Taz, which are transcriptional co-activators. When the Hippo pathway is activated, Yap/Taz are phosphorylated, leading to cytoplasmic retention and degradation, and diminishing their transcriptional activity. Yap has also been recently implicated as a potential oncogene, as it is upregulated and transcriptionally active in several tumor types. Furthermore, inhibiting Yap activity in various cancer models has been shown to revert cancer cells to a normal phenotype. Although the role of Yap has been described in several organ systems, there is a paucity of information about the function of Yap in the central nervous system. I investigated the function of Yap/Taz in the murine cerebellum to determine its significance during normal development and a potential role for Yap/Taz in medulloblastoma, a tumor that arises in the cerebellum. In Chapter 2, I describe the expression pattern of Yap from embryonic through adult stages in mice, and demonstrate the functional significance of Yap/Taz in different cell populations using conditional knockout mouse models. I show that Yap plays a significant role in cell fate determination as well as in cerebellar foliation: Yap is highly expressed in the ventricular zone and is required for the proper formation of ependymal cells, and is also strongly expressed in Bergmann glia (BG) during early developmental stages, where Yap, together with Taz, plays a significant role in cerebellar foliation. Furthermore, Yap/Taz-deficient BG exhibit migrational defects, as their cell bodies can be found mislocalized to the molecular layer (ML), rather than remaining tightly associated with Purkinje Cells (PCs) in the PC layer. BG support the health of PCs, and severely defective BG positioning eventually leads to a loss of PCs. However, although Yap is highly expressed in granule neuron progenitors (GNPs) during the rapid postnatal expansion stage, it does not appear to play a major role in proliferation of these cells as conditionally knocking-out Yap/Taz in GNPs does not alter their proliferative capacity. Our observations demonstrate that in the cerebellum, Yap has a novel function in glia that is required for the development of normal foliation and organization, but plays a minimal role in GNP proliferation. Importantly, I also show that the reduction of sphingosine-1-phosphate G-protein-coupled receptor (S1P1) signal transduction activates the upstream kinase Lats with concomitant increases of phosphorylated Yap as well as a reduction of the known Yap target connective tissue growth factor (CTGF). This study identifies a novel function of Yap/Taz in cerebellar glia that is required for the development of normal foliation and laminar organization with sphingosine-1-phosphate (S1P) signaling as a potential extracellular cue regulating Yap activity during cerebellar development. In Chapter 3, I present further support for the finding that Yap/Taz are not required for GNP proliferation in vivo by discussing the failure of Yap/Taz loss to rescue the Sonic-hedgehog (Shh) mediated medulloblastoma phenotype, in which GNPs are considered to be the tumor cell of origin. Furthermore, I provide evidence suggestive of a tumor suppressive function of Yap/Taz in the cerebellum. Together, previously unknown functions of Yap in the developing and malignant cerebellum are described, providing a foundation for future studies of Yap in the central nervous system (CNS).
Temple University--Theses

Des études épidémiologiques et expérimentales suggèrent que la progression de la maladie rénale chronique (MRC) après une lésion initiale est génétiquement déterminée, mais les réseaux génétiques qui contribuent à cette prédisposition restent inconnus. Parmi les voies moléculaires potentielles impliquées dans la MRC, cette étude s'est concentrée sur la voie Hippo, une cascade de signalisation conservée au cours de l'évolution et cruciale pour la régulation de la taille des organes et de la prolifération cellulaire. Les protéines paralogues YAP et TAZ, deux coactivateurs transcriptionnels de la voie Hippo, ont récemment été identifiées comme étant également des mécanosenseurs, capables de détecter un large éventail de signaux mécaniques et de les traduire en programmes transcriptionnels spécifiques aux cellules. L'activation de YAP et TAZ a été impliquée dans la progression de plusieurs maladies rénales et dans la transition de la lésion rénale aiguë (LRA) à la MRC . Cependant, les mécanismes sous-jacents restent obscurs et leur rôle dans des conditions physiologiques n'est pas encore bien compris. L'objectif de ce projet est d'élucider le rôle de YAP et TAZ dans les tubules rénaux. Tout d'abord, en utilisant la combinaison de modèles de souris transgéniques et de néphrectomie comme modèle de MRC, nous avons étudié l'effet de l'inactivation sélective du gène Yap ou Taz dans les cellules tubulaires rénales dans ce contexte de maladie. Nos résultats ont révélé une redondance potentielle entre ces deux protéines dans les cellules épithéliales tubulaires. Il est intéressant de noter que nos souris déficientes à la fois en YAP et en TAZ ont développé spontanément un phénotype rénal sévère avec des lésions tubulaires, de la fibrose et de l'inflammation, qui a été décrit en détail dans ce travail. Grâce à l'analyse transcriptomique, nous avons identifié une nouvelle signature moléculaire qui pourrait permettre de mieux comprendre les mécanismes régulés par YAP et TAZ dans les cellules tubulaires. Paradoxalement, dans notre modèle de double knock-out, nous avons observé une aggravation de l'expression et de l'activation de YAP et TAZ, parallèlement à la progression des lésions. Ceci semble être le résultat d'une expansion des cellules « non recombinées », montrant les rôles complexes de YAP et TAZ dans la communication avec les cellules voisines. Ces données démontrent le rôle essentiel de YAP et TAZ dans le maintien de l'homéostasie tubulaire et l'équilibre complexe nécessaire à leur régulation. Cette complexité peut avoir des implications pour les stratégies thérapeutiques ciblant l'inhibition de YAP et TAZ dans les maladies rénales, surtout si l'on considère les effets secondaires potentiels qui pourraient rendre ces approches plus difficiles
Epidemiological and experimental studies suggest that the progression of Chronic Kidney Disease (CKD) after an initial injury is genetically determined, but the genetic networks that contribute to this predisposition remain unknown. Among the potential molecular pathways involved in CKD, this study focused on the Hippo pathway, an evolutionarily conserved signaling cascade crucial for regulating organ size and cell proliferation. The paralogs proteins YAP and TAZ, two transcriptional coactivators of the Hippo pathway, have recently been identified also as mechanosensors, capable of detecting a wide range of mechanical cues and translating them into cell-specific transcriptional programs. Activation of YAP and TAZ has been implicated to the progression of several kidney diseases and in the transition from acute kidney injury (AKI) to CKD. However, the underlying mechanisms remain unclear and their role under physiological conditions is still not well understood. The aim of this project is to elucidate the role of YAP and TAZ in the renal tubules. First, using the combination of inducing transgenic mouse models and nephrectomy as a model of CKD, we investigated the effect of the selective inactivation of Yap or Taz gene in renal tubular cells in this disease context. Our findings revealed a potential redundancy between these two proteins in tubular epithelial cells. Interestingly, our mice deficient in both YAP and TAZ developed a spontaneous severe renal phenotype with tubular injury, fibrosis and inflammation, which was described in detail in this work. Through transcriptomic analysis, we identified a new novel molecular signature that may provide further insight into the mechanisms regulated by YAP and TAZ in tubular cells. Paradoxically, in our double knock-out model, we observed a worsening of YAP and TAZ expression and activation, in parallel with the lesion progression. This appeared to be the result of an expansion of the "non-recombined" cells, showing the complex roles of YAP and TAZ in the cross-talk with the neighbouring cells. These data demonstrated the essential role of YAP and TAZ in maintaining tubular homeostasis and the intricate balance required for their regulation. This complexity may have implications for therapeutic strategies targeting the inhibition of YAP and TAZ in kidney disease, especially considering the potential side effects that could make such approaches more challenging