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1
Li, Ruojun, and Weiqiang Huang. "Yes-Associated Protein and Transcriptional Coactivator with PDZ-Binding Motif in Cardiovascular Diseases." International Journal of Molecular Sciences 24, no. 2 (January 14, 2023): 1666. http://dx.doi.org/10.3390/ijms24021666.
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Yes-associated protein (YAP, also known as YAP1) and its paralogue TAZ (with a PDZ-binding motif) are transcriptional coactivators that switch between the cytoplasm and nucleus and regulate the organ size and tissue homeostasis. This review focuses on the research progress on YAP/TAZ signaling proteins in myocardial infarction, cardiac remodeling, hypertension and coronary heart disease, cardiomyopathy, and aortic disease. Based on preclinical studies on YAP/TAZ signaling proteins in cellular/animal models and clinical patients, the potential roles of YAP/TAZ proteins in some cardiovascular diseases (CVDs) are summarized.
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Makita, Ryosuke, Yasunobu Uchijima, Koichi Nishiyama, Tomokazu Amano, Qin Chen, Takumi Takeuchi, Akihisa Mitani, et al. "Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ." American Journal of Physiology-Renal Physiology 294, no. 3 (March 2008): F542—F553. http://dx.doi.org/10.1152/ajprenal.00201.2007.
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TAZ (transcriptional coactivator with PDZ-binding motif), also called WWTR1 (WW domain containing transcription regulator 1), is a 14-3-3-binding molecule homologous to Yes-associated protein. TAZ acts as a coactivator for several transcription factors as well as a modulator of membrane-associated PDZ domain-containing proteins, but its (patho)physiological roles remain unknown. Here we show that gene inactivation of TAZ in mice resulted in pathological changes in the kidney and lung that resemble the common human diseases polycystic kidney disease and pulmonary emphysema. Taz-null/ lacZ knockin mutant homozygotes demonstrated renal cyst formation as early as embryonic day 15.5 with dilatation of Bowman's capsules and proximal tubules, followed by pelvic dilatation and hydronephrosis. After birth, only one-fifth of TAZ-deficient homozygotes grew to adulthood and demonstrated multicystic kidneys with severe urinary concentrating defects and polyuria. Furthermore, adult TAZ-deficient homozygotes exhibited diffuse emphysematous changes in the lung. Thus TAZ is essential for developmental mechanisms involved in kidney and lung organogenesis, whose disturbance may lead to the pathogenesis of common human diseases.
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Meng, Xianwang, Vishnuka D. Arulsundaram, Ahmed F. Yousef, Paul Webb, John D. Baxter, Joe S. Mymryk, and Paul G. Walfish. "Corepressor/Coactivator Paradox: Potential Constitutive Coactivation by Corepressor Splice Variants." Nuclear Receptor Signaling 4, no. 1 (January 2006): nrs.04022. http://dx.doi.org/10.1621/nrs.04022.
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The functional consequences of the interaction of transcriptional coregulators with the human thyroid hormone receptor (TR) in mammalian cells are complex. We have used the yeast, Saccharomyces cerevisiae, which lack endogenous nuclear receptors (NRs) and NR coregulators, as a model to decipher mechanisms regulating transcriptional activation by TR. In effect, this system allows the reconstitution of TR mediated transcription complexes by the expression of specific combinations of mammalian proteins in yeast. In this yeast system, human adenovirus 5 early region 1A (E1A), a natural N-CoR splice variant (N-CoRI) or an artificial N-CoR truncation (N-CoRC) coactivate unliganded TRs and these effects are inhibited by thyroid hormone (TH). E1A contains a short peptide sequence that resembles known corepressor-NR interaction motifs (CoRNR box motif, CBM), and this motif is required for TR binding and coactivation. N-CoRI and N-CoRC contain three CBMs, but only the C-terminal CBM1 is critical for coactivation. These observations in a yeast model system suggest that E1A and N-CoRI are naturally occurring TR coactivators that bind in the typical corepressor mode. These findings also raise the possibility that alternative splicing events which form corepressor proteins containing only C-terminal CBM motifs could represent a novel mechanism in mammalian cells for regulating constitutive transcriptional activation by TRs.
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Wang, Kainan, Cindy Degerny, Minghong Xu, and Xiang-Jiao Yang. "YAP, TAZ, and Yorkie: a conserved family of signal-responsive transcriptional coregulators in animal development and human diseaseThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process." Biochemistry and Cell Biology 87, no. 1 (February 2009): 77–91. http://dx.doi.org/10.1139/o08-114.
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How extracellular cues are transduced to the nucleus is a fundamental issue in biology. The paralogous WW-domain proteins YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif; also known as WWTR1, for WW-domain containing transcription regulator 1) constitute a pair of transducers linking cytoplasmic signaling events to transcriptional regulation in the nucleus. A cascade composed of mammalian Ste20-like (MST) and large tumor suppressor (LATS) kinases directs multisite phosphorylation, promotes 14-3-3 binding, and hinders nuclear import of YAP and TAZ, thereby inhibiting their transcriptional coactivator and growth-promoting activities. A similar cascade regulates the trafficking and function of Yorkie, the fly orthologue of YAP. Mammalian YAP and TAZ are expressed in various tissues and serve as coregulators for transcriptional enhancer factors (TEFs; also referred to as TEADs, for TEA-domain proteins), runt-domain transcription factors (Runxs), peroxisome proliferator-activated receptor γ (PPARγ), T-box transcription factor 5 (Tbx5), and several others. YAP and TAZ play distinct roles during mouse development. Both, and their upstream regulators, are intimately linked to tumorigenesis and other pathogenic processes. Here, we review studies on this family of signal-responsive transcriptional coregulators and emphasize how relative sequence conservation predicates their function and regulation, to provide a conceptual framework for organizing available information and seeking new knowledge about these signal transducers.
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Ma, Han, Heng Hong, Shih-Ming Huang, Ryan A. Irvine, Paul Webb, Peter J. Kushner, Gerhard A. Coetzee, and Michael R. Stallcup. "Multiple Signal Input and Output Domains of the 160-Kilodalton Nuclear Receptor Coactivator Proteins." Molecular and Cellular Biology 19, no. 9 (September 1, 1999): 6164–73. http://dx.doi.org/10.1128/mcb.19.9.6164.
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ABSTRACT Members of the 160-kDa nuclear receptor coactivator family (p160 coactivators) bind to the conserved AF-2 activation function found in the hormone binding domains of nuclear receptors (NR) and are potent transcriptional coactivators for NRs. Here we report that the C-terminal region of p160 coactivators glucocorticoid receptor interacting protein 1 (GRIP1), steroid receptor coactivator 1 (SRC-1a), and SRC-1e binds the N-terminal AF-1 activation function of the androgen receptor (AR), and p160 coactivators can thereby enhance transcriptional activation by AR. While they all interact efficiently with AR AF-1, these same coactivators have vastly different binding strengths with and coactivator effects on AR AF-2. p160 activation domain AD1, which binds secondary coactivators CREB binding protein (CBP) and p300, was previously implicated as the principal domain for transmitting the activating signal to the transcription machinery. We identified a new highly conserved motif in the AD1 region which is important for CBP/p300 binding. Deletion of AD1 only partially reduced p160 coactivator function, due to signaling through AD2, another activation domain located at the C-terminal end of p160 coactivators. C-terminal coactivator fragments lacking AD1 but containing AD2 and the AR AF-1 binding site served as efficient coactivators for full-length AR and AR AF-1. The two signal input domains (one that binds NR AF-2 domains and one that binds AF-1 domains of some but not all NRs) and the two signal output domains (AD1 and AD2) of p160 coactivators played different relative roles for two different NRs: AR and thyroid hormone receptor.
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Cherrett, Claire, Makoto Furutani-Seiki, and Stefan Bagby. "The Hippo pathway: key interaction and catalytic domains in organ growth control, stem cell self-renewal and tissue regeneration." Essays in Biochemistry 53 (August 28, 2012): 111–27. http://dx.doi.org/10.1042/bse0530111.
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The Hippo pathway is a conserved pathway that interconnects with several other pathways to regulate organ growth, tissue homoeostasis and regeneration, and stem cell self-renewal. This pathway is unique in its capacity to orchestrate multiple processes, from sensing to execution, necessary for organ expansion. Activation of the Hippo pathway core kinase cassette leads to cytoplasmic sequestration of the nuclear effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), consequently disabling their transcriptional co-activation function. Components upstream of the core kinase cassette have not been well understood, especially in vertebrates, but are gradually being elucidated and include cell polarity and cell adhesion proteins.
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Mak, Ho Yi, Sue Hoare, Pirkko M. A. Henttu, and Malcolm G. Parker. "Molecular Determinants of the Estrogen Receptor-Coactivator Interface." Molecular and Cellular Biology 19, no. 5 (May 1, 1999): 3895–903. http://dx.doi.org/10.1128/mcb.19.5.3895.
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ABSTRACT Transcriptional activation by the estrogen receptor is mediated through its interaction with coactivator proteins upon ligand binding. By systematic mutagenesis, we have identified a group of conserved hydrophobic residues in the ligand binding domain that are required for binding the p160 family of coactivators. Together with helix 12 and lysine 366 at the C-terminal end of helix 3, they form a hydrophobic groove that accommodates an LXXLL motif, which is essential for mediating coactivator binding to the receptor. Furthermore, we demonstrated that the high-affinity binding of motif 2, conserved in the p160 family, is due to the presence of three basic residues N terminal to the core LXXLL motif. The recruitment of p160 coactivators to the estrogen receptor is therefore likely to depend not only on the LXXLL motif making hydrophobic interactions with the docking surface on the receptor, but also on adjacent basic residues, which may be involved in the recognition of charged residues on the receptor to allow the initial docking of the motif.
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Rachez, Christophe, Matthew Gamble, Chao-Pei Betty Chang, G. Brandon Atkins, Mitchell A. Lazar, and Leonard P. Freedman. "The DRIP Complex and SRC-1/p160 Coactivators Share Similar Nuclear Receptor Binding Determinants but Constitute Functionally Distinct Complexes." Molecular and Cellular Biology 20, no. 8 (April 15, 2000): 2718–26. http://dx.doi.org/10.1128/mcb.20.8.2718-2726.2000.
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ABSTRACT Transcriptional activation requires both access to DNA assembled as chromatin and functional contact with components of the basal transcription machinery. Using the hormone-bound vitamin D3receptor (VDR) ligand binding domain (LBD) as an affinity matrix, we previously identified a novel multisubunit coactivator complex, DRIP (VDR-interacting proteins), required for transcriptional activation by nuclear receptors and several other transcription factors. In this report, we characterize the nuclear receptor binding features of DRIP205, a key subunit of the DRIP complex, that interacts directly with VDR and thyroid hormone receptor in response to ligand and anchors the other DRIP subunits to the nuclear receptor LBD. In common with other nuclear receptor coactivators, DRIP205 interaction occurs through one of two LXXLL motifs and requires the receptor's AF-2 subdomain. Although the second motif of DRIP205 is required only for VDR binding in vitro, both motifs are used in the context of an retinoid X receptor-VDR heterodimer on DNA and in transactivation in vivo. We demonstrate that both endogenous p160 coactivators and DRIP complexes bind to the VDR LBD from nuclear extracts through similar sequence requirements, but they do so as distinct complexes. Moreover, in contrast to the p160 family of coactivators, the DRIP complex is devoid of any histone acetyltransferase activity. The results demonstrate that different coactivator complexes with distinct functions bind to the same transactivation region of nuclear receptors, suggesting that they are both required for transcription activation by nuclear receptors.
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Pankratova, Maria D., Andrei A. Riabinin, Elizaveta A. Butova, Arseniy V. Selivanovskiy, Elena I. Morgun, Sergey V. Ulianov, Ekaterina A. Vorotelyak, and Ekaterina P. Kalabusheva. "YAP/TAZ Signalling Controls Epidermal Keratinocyte Fate." International Journal of Molecular Sciences 25, no. 23 (November 30, 2024): 12903. https://doi.org/10.3390/ijms252312903.
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The paralogues Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) control cell proliferation and cell fate determination from embryogenesis to ageing. In the skin epidermis, these proteins are involved in both homeostatic cell renewal and injury-induced regeneration and also drive carcinogenesis and other pathologies. YAP and TAZ are usually considered downstream of the Hippo pathway. However, they are the central integrating link for the signalling microenvironment since they are involved in the interplay with signalling cascades induced by growth factors, cytokines, and physical parameters of the extracellular matrix. In this review, we summarise the evidence on how YAP and TAZ are activated in epidermal keratinocytes; how YAP/TAZ-mediated signalling cooperates with other signalling molecules at the plasma membrane, cytoplasmic, and nuclear levels; and how YAP/TAZ ultimately controls transcription programmes, defining epidermal cell fate.
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Huang, SM, CJ Huang, WM Wang, JC Kang, and WC Hsu. "The enhancement of nuclear receptor transcriptional activation by a mouse actin-binding protein, alpha actinin 2." Journal of Molecular Endocrinology 32, no. 2 (April 1, 2004): 481–96. http://dx.doi.org/10.1677/jme.0.0320481.
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The p160 coactivators, steroid receptor coactivator 1, glucocorticoid receptor interacting protein 1 (GRIP1) and the activator of thyroid and retinoic acid receptor, have two activation domains, AD1 and AD2, which transmit the activation signal from the DNA-bound nuclear receptor to the chromatin and/or transcription machinery. In screening for mammalian proteins that bind the AD2 of GRIP1, we identified a mouse actin-binding protein, alpha actinin 2 (mACTN2). mACTN2 was expressed in the heart, skeletal muscle, lung, brain and testis, but there was no expression in the spleen, liver or kidney. Interestingly, the expression level of mACTN2 in the developing embryo depended on the embryonic stage. We further demonstrated that mACTN2 could enhance two transactivation activities of GRIP1, which in turn could enhance the homodimerization of mACTN2. Importantly, mACTN2 not only served as a primary coactivator for androgen receptor, estrogen receptor and thyroid receptor activities, but also acted synergistically with GRIP1 to enhance these nuclear receptor (NR) functions. However, the NR binding motif, LXXLL, conserved in mACTN2 and other actinin family proteins, might be a dispensable domain for its coactivator roles in NRs. These findings suggested that mACTN2 might play an important role in GRIP1-induced NR coactivator functions.
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Tóth, Marcell, Shan Wan, Jennifer Schmitt, Patrizia Birner, Teng Wei, Fabian von Bubnoff, Carolina de la Torre, et al. "The Cell Polarity Protein MPP5/PALS1 Controls the Subcellular Localization of the Oncogenes YAP and TAZ in Liver Cancer." International Journal of Molecular Sciences 26, no. 2 (January 14, 2025): 660. https://doi.org/10.3390/ijms26020660.
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The oncogenes yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are potent liver oncogenes. Because gene mutations cannot fully explain their nuclear enrichment, we aim to understand which mechanisms cause YAP/TAZ activation in liver cancer cells. The combination of proteomics and functional screening identified numerous apical cell polarity complex proteins interacting with YAP and TAZ. Co-immunoprecipitation (Co-IP) experiments confirmed that membrane protein palmitoylated 5 (MPP5; synonym: PALS1) physically interacts with YAP and TAZ. After removing different MPP5 protein domains, Co-IP analyses revealed that the PDZ domain plays a crucial role in YAP binding. The interaction between YAP and MPP5 in the cytoplasm of cancer cells was demonstrated by proximity ligation assays (PLAs). In human hepatocellular carcinoma (HCC) tissues, a reduction in apical MPP5 expression was observed, correlating with the nuclear accumulation of YAP and TAZ. Expression data analysis illustrated that MPP5 is inversely associated with YAP/TAZ target gene signatures in human HCCs. Low MPP5 levels define an HCC patient group with a poor clinical outcome. In summary, MPP5 facilitates the nuclear exclusion of YAP and TAZ in liver cancer. This qualifies MPP5 as a potential tumor-suppressor gene and explains how changes in cell polarity can foster tumorigenesis.
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Goo, Young-Hwa, Young Chang Sohn, Dae-Hwan Kim, Seung-Whan Kim, Min-Jung Kang, Dong-Ju Jung, Eunyee Kwak, et al. "Activating Signal Cointegrator 2 Belongs to a Novel Steady-State Complex That Contains a Subset of Trithorax Group Proteins." Molecular and Cellular Biology 23, no. 1 (January 1, 2003): 140–49. http://dx.doi.org/10.1128/mcb.23.1.140-149.2003.
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ABSTRACT Many transcription coactivators interact with nuclear receptors in a ligand- and C-terminal transactivation function (AF2)-dependent manner. These include activating signal cointegrator 2 (ASC-2), a recently isolated transcriptional coactivator molecule, which is amplified in human cancers and stimulates transactivation by nuclear receptors and numerous other transcription factors. In this report, we show that ASC-2 belongs to a steady-state complex of approximately 2 MDa (ASC-2 complex [ASCOM]) in HeLa nuclei. ASCOM contains retinoblastoma-binding protein RBQ-3, α/β-tubulins, and trithorax group proteins ALR-1, ALR-2, HALR, and ASH2. In particular, ALR-1/2 and HALR contain a highly conserved 130- to 140-amino-acid motif termed the SET domain, which was recently implicated in histone H3 lysine-specific methylation activities. Indeed, recombinant ALR-1, HALR, and immunopurified ASCOM exhibit very weak but specific H3-lysine 4 methylation activities in vitro, and transactivation by retinoic acid receptor appears to involve ligand-dependent recruitment of ASCOM and subsequent transient H3-lysine 4 methylation of the promoter region in vivo. Thus, ASCOM may represent a distinct coactivator complex of nuclear receptors. Further characterization of ASCOM will lead to a better understanding of how nuclear receptors and other transcription factors mediate transcriptional activation.
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Chen, Guangyuan, Ping Huang, Jiabin Xie, and Rihong Li. "Overexpression of transcriptional co-activator with PDZ-binding motif promotes epithelial mesenchymal transformation of ovarian cancer cells by upregulating Smad3 and Snail1." Materials Express 10, no. 1 (January 1, 2020): 120–26. http://dx.doi.org/10.1166/mex.2020.1617.
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This study is intended to explore the effect of transcriptional coactivator with PDZ binding motif (TAZ) expression in ovarian cancer cells as well as investigate the expression of signal proteins Smad3 and Snail1. Ovarian cancer cells (SKOV-3) were divided into two groups: control and TAZ overexpression. The overexpression of TAZ in SKOV-3 cells was determined by immunofluorescence, western blot, and qRT-PCR. The proliferation, invasiveness, and expression of epithelial mesenchymal transformation (EMT)-associated proteins were detected, and the expression of Smad3 and Snail1 proteins was determined by qRT-PCR and western blot, respectively. Small interfering RNA (siRNA) targeting TAZ were synthesized and used to transfect SKOV-3. Cell migration and invasion were observed via a wound healing assay and a transwell assay, respectively. The expressions of representative genes involved in proliferation and migration, EMT-associated proteins and Smad3 and Snail1 proteins were also detected by western blot assays. The results of qRT-PCR, immunofluorescence, and western blot showed that, compared with the control group, the expressions of Smad3 and Snail1 protein were upregulated, and the expression of EMT-related genes-including Actin, N-cadherin, and Vimentin protein-was downregulated in the TAZ overexpression group. After TAZ mRNA was suppressed, the migration and invasion ability of the TAZ siRNA group was weaker than that of the control group. In addition, the expression level of Smad3 and Snail1 decreased when TAZ was silenced, while the expression of EMT-related genes increased. Therefore, TAZ in ovarian cancer cells can promote growth, migration, and invasiveness of cancer cells by regulating genes related to proliferation, migration, and invasion.
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Goli, Zahra, Iraj Khodadadi, Jamshid Karimi, Sina Mohagheghi, and Heidar Tavilani. "Expression of Integrin β1, Focal Adhesion Kinase, and PDZ-Binding Motif in Human Liver Cirrhosis and Simple Steatosis." Avicenna Journal of Medical Biochemistry 10, no. 2 (December 18, 2022): 142–47. http://dx.doi.org/10.34172/ajmb.2022.2354.
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Background: Integrins are transmembrane mechanosensitive proteins that negatively contribute to the pathogenesis of different types of chronic liver disease and can activate focal adhesion kinase (FAK). Objectives: This study aimed to determine the hepatic integrin β1 and FAK mRNA as well as the transcriptional coactivator with PDZ-binding motif (TAZ) protein expressions in cirrhotic patients and simple steatosis. Methods: In this case–control study, liver tissues were collected from 30 cirrhotic patients with various etiologies (i.e., nonalcoholic steatohepatitis-, primary sclerosing cholangitis-, alcoholic-, autoimmune hepatitis [AIH]- and hepatitis B virus [HBV]/hepatitis C virus [HCV]-related cirrhosis [six per group]), liver samples with simple steatosis (n=6), and control liver tissues (n=9). Results: Integrin β1 gene expression was significantly up-regulated in all cirrhotic groups compared to control group (P<0.05), with the exception of AIH cirrhosis. However, hepatic FAK gene expression and TAZ protein level in the cirrhotic groups were not significantly different than those in the control group. Furthermore, hepatic integrin β1 and FAK gene expressions as well as TAZ protein level in simple steatosis were significantly lower than those in nonalcoholic steatohepatitis (NASH) cirrhosis and control (P<0.05). Conclusion: Integrin β1 was up-regulated in cirrhotic liver tissues. In addition, FAK, integrin β1, and TAZ were concordantly down-regulated in simple steatosis, and may have been involve in the steatosis development.
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Pseftogas, Athanasios, Konstantinos Xanthopoulos, Theofilos Poutahidis, Chrysanthi Ainali, Dimitra Dafou, Emmanuel Panteris, Joseph G. Kern, et al. "The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling." Cancers 12, no. 8 (July 24, 2020): 2047. http://dx.doi.org/10.3390/cancers12082047.
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Downregulation of the cylindromatosis (CYLD) tumor suppressor has been associated with breast cancer development and progression. Here, we report a critical role for CYLD in maintaining the phenotype of mammary epithelial cells in vitro and in vivo. CYLD downregulation or inactivation induced an epithelial to mesenchymal transition of mammary epithelial cells that was dependent on the concomitant activation of the transcription factors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and transforming growth factor beta (TGFβ)signaling. CYLD inactivation enhanced the nuclear localization of YAP/TAZ and the phosphorylation of Small Mothers Against Decapentaplegic (SMAD)2/3 proteins in confluent cell culture conditions. Consistent with these findings were the hyperplastic alterations of CYLD-deficient mouse mammary epithelia, which were associated with enhanced nuclear expression of the YAP/TAZ transcription factors. Furthermore, in human breast cancer samples, downregulation of CYLD expression correlates with enhanced YAP/TAZ-regulated target gene expression. Our results identify CYLD as a critical regulator of a signaling node that prevents the coordinated activation of YAP/TAZ and the TGFβ pathway in mammary epithelial cells, in order to maintain their phenotypic identity and homeostasis. Consequently, they provide a novel conceptual framework that supports and explains a causal implication of deficient CYLD expression in aggressive human breast cancers.
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Major, Michael L., Rita Lepe, and Robert H. Costa. "Forkhead Box M1B Transcriptional Activity Requires Binding of Cdk-Cyclin Complexes for Phosphorylation-Dependent Recruitment of p300/CBP Coactivators." Molecular and Cellular Biology 24, no. 7 (April 1, 2004): 2649–61. http://dx.doi.org/10.1128/mcb.24.7.2649-2661.2004.
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ABSTRACT Previous liver regeneration studies demonstrated that the mouse forkhead box M1B (FoxM1B) transcription factor regulates hepatocyte proliferation through expression of cell cycle genes that stimulate cyclin-dependent kinase 2 (Cdk2) and Cdk1 activity. In this study, we demonstrated that disruption of the FoxM1B Cdk1/2 phosphorylation site at Thr residue 596 significantly reduced both FoxM1B transcriptional activity and Cdk phosphorylation of the FoxM1B T596A mutant protein in vivo. Retention of this FoxM1B 596 Cdk phosphorylation site was found to be essential for recruiting the histone acetyltransferase CREB binding protein (CBP) to the FoxM1B transcriptional activation domain. Consistent with these findings, dominant negative Cdk1 protein significantly reduced FoxM1B transcriptional activity and inhibited FoxM1B recruitment of the CBP coactivator protein. Likewise, Cdc25B-mediated stimulation of Cdk activity together with elevated levels of the CBP coactivator protein provided a 6.2-fold synergistic increase in FoxM1B transcriptional activity. Furthermore, mutation of the FoxM1B Leu 641 residue within an LXL motif (residues 639 to 641) inhibited recruitment of Cdk-cyclin complexes and caused significant reduction in both FoxM1B transcriptional activity and in vivo Cdk phosphorylation of the FoxM1B Thr 596 residue. We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins.
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Gargini, Ricardo, Berta Segura-Collar, Beatriz Herránz, Vega García-Escudero, Andrés Romero-Bravo, Felipe J. Núñez, Daniel García-Pérez, et al. "The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas." Science Translational Medicine 12, no. 527 (January 22, 2020): eaax1501. http://dx.doi.org/10.1126/scitranslmed.aax1501.
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Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU (MAPT), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, MAPT was almost absent from tumors with epidermal growth factor receptor (EGFR) mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) EGFR. We demonstrated that the overexpression of TAU, through the stabilization of microtubules, impaired the mesenchymal/pericyte-like transformation of glioma cells by blocking EGFR, nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and the transcriptional coactivator with PDZ-binding motif (TAZ). Our data also showed that mut EGFR induced a constitutive activation of this pathway, which was no longer sensitive to TAU. By inhibiting the transdifferentiation capacity of EGFRamp/wt tumor cells, TAU protein inhibited angiogenesis and favored vascular normalization, decreasing glioma aggressiveness and increasing their sensitivity to chemotherapy.
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Sharma, Jyoti, and Pavneesh Madan. "Characterisation of the Hippo signalling pathway during bovine preimplantation embryo development." Reproduction, Fertility and Development 32, no. 4 (2020): 392. http://dx.doi.org/10.1071/rd18320.
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Blastocyst formation is an important milestone during preimplantation embryo development. During murine preimplantation embryogenesis, the Hippo signalling pathway is known to play a significant role in lineage segregation and henceforth the formation of blastocysts. However, the role of this cell signalling pathway during bovine embryogenesis remains unknown. Thus, the aim of the present study was to characterise the Hippo signalling pathway during bovine preimplantation embryo development. mRNA transcripts of Hippo signalling pathway constituents (i.e. crumbs cell polarity complex component 3 (CRB3), mammalian sterile 20-like 1 (MST1), mammalian sterile 20-like 2 (MST2), Yes associated protein 1 (YAP1), transcriptional coactivator with PDZ-binding motif (TAZ)) were observed during all stages of bovine preimplantation embryo development. To evaluate the localisation of Hippo pathway components, bovine embryos at timed stages of development were stained using specific antibodies and observed under a laser confocal microscope. Although MST1/2 proteins were in the cytoplasm during various stages of bovine embryonic development, TAZ and phosphorylated (p-) YAP were detected in the nucleus during the blastocyst stages. Localisation of TAZ and p-YAP proteins was distinct in the bovine compared with mouse model, suggesting that the Hippo signalling pathway is regulated differently in early bovine embryos.
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Haak, Andrew J., Enis Kostallari, Delphine Sicard, Giovanni Ligresti, Kyoung Moo Choi, Nunzia Caporarello, Dakota L. Jones, et al. "Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis." Science Translational Medicine 11, no. 516 (October 30, 2019): eaau6296. http://dx.doi.org/10.1126/scitranslmed.aau6296.
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Tissue fibrosis is characterized by uncontrolled deposition and diminished clearance of fibrous connective tissue proteins, ultimately leading to organ scarring. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) have recently emerged as pivotal drivers of mesenchymal cell activation in human fibrosis. Therapeutic strategies inhibiting YAP and TAZ have been hindered by the critical role that these proteins play in regeneration and homeostasis in different cell types. Here, we find that the Gαs-coupled dopamine receptor D1 (DRD1) is preferentially expressed in lung and liver mesenchymal cells relative to other resident cells of these organs. Agonism of DRD1 selectively inhibits YAP/TAZ function in mesenchymal cells and shifts their phenotype from profibrotic to fibrosis resolving, reversing in vitro extracellular matrix stiffening and in vivo tissue fibrosis in mouse models. Aromatic l-amino acid decarboxylase [DOPA decarboxylase (DDC)], the enzyme responsible for the final step in biosynthesis of dopamine, is decreased in the lungs of subjects with idiopathic pulmonary fibrosis, and its expression inversely correlates with disease severity, consistent with an endogenous protective role for dopamine signaling that is lost in pulmonary fibrosis. Together, these findings establish a pharmacologically tractable and cell-selective approach to targeting YAP/TAZ via DRD1 that reverses fibrosis in mice.
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Shao, Wenlin, Shlomit Halachmi, and Myles Brown. "ERAP140, a Conserved Tissue-Specific Nuclear Receptor Coactivator." Molecular and Cellular Biology 22, no. 10 (May 15, 2002): 3358–72. http://dx.doi.org/10.1128/mcb.22.10.3358-3372.2002.
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ABSTRACT We report here the identification and characterization of a novel nuclear receptor coactivator, ERAP140. ERAP140 was isolated in a screen for ERα-interacting proteins using the ERα ligand binding domain as a probe. The ERAP140 protein shares no sequence and has little structural homology with other nuclear receptor cofactors. However, homologues of ERAP140 have been identified in mouse, Drosophila, and Caenorhabditis elegans. The expression of ERAP140 is cell and tissue type specific and is most abundant in the brain, where its expression is restricted to neurons. In addition to interacting with ERα, ERAP140 also binds ERβ, TRβ, PPARγ, and RARα. ERAP140 interacts with ERα via a noncanonical interaction motif. The ERα-ERAP140 association can be competed by coactivator NR boxes, indicating ERAP140 binds ERα on a surface similar to that of other coactivators. ERAP140 can enhance the transcriptional activities of nuclear receptors with which it interacts. In vivo, ERAP140 is recruited by estrogen-bound ERα to the promoter region of endogenous ERα target genes. Furthermore, the E2-induced recruitment of ERAP140 to the promoter follows a cyclic pattern similar to that of other coactivators. Our results suggest that ERAP140 represents a distinct class of nuclear receptor coactivators that mediates receptor signaling in specific target tissues.
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Liu, Fei, David Lagares, Kyoung Moo Choi, Lauren Stopfer, Aleksandar Marinković, Vladimir Vrbanac, Clemens K. Probst, et al. "Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis." American Journal of Physiology-Lung Cellular and Molecular Physiology 308, no. 4 (February 15, 2015): L344—L357. http://dx.doi.org/10.1152/ajplung.00300.2014.
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Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis.
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Andersson, Ulf, and Richard C. Scarpulla. "PGC-1-Related Coactivator, a Novel, Serum-Inducible Coactivator of Nuclear Respiratory Factor 1-Dependent Transcription in Mammalian Cells." Molecular and Cellular Biology 21, no. 11 (June 1, 2001): 3738–49. http://dx.doi.org/10.1128/mcb.21.11.3738-3749.2001.
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ABSTRACT The thermogenic peroxisome proliferator-activated receptor γ (PPAR-γ) coactivator 1 (PGC-1) has previously been shown to activate mitochondrial biogenesis in part through a direct interaction with nuclear respiratory factor 1 (NRF-1). In order to identify related coactivators that act through NRF-1, we searched the databases for sequences with similarities to PGC-1. Here, we describe the first characterization of a 177-kDa transcriptional coactivator, designated PGC-1-related coactivator (PRC). PRC is ubiquitously expressed in murine and human tissues and cell lines; but unlike PGC-1, PRC was not dramatically up-regulated during thermogenesis in brown fat. However, its expression was down-regulated in quiescent BALB/3T3 cells and was rapidly induced by reintroduction of serum, conditions where PGC-1 was not detected. PRC activated NRF-1-dependent promoters in a manner similar to that observed for PGC-1. Moreover, NRF-1 was immunoprecipitated from cell extracts by antibodies directed against PRC, and both proteins were colocalized to the nucleoplasm by confocal laser scanning microscopy. PRC interacts in vitro with the NRF-1 DNA binding domain through two distinct recognition motifs that are separated by an unstructured proline-rich region. PRC also contains a potent transcriptional activation domain in its amino terminus adjacent to an LXXLL motif. The spatial arrangement of these functional domains coincides with those found in PGC-1, supporting the conclusion that PRC and PGC-1 are structurally and functionally related. We conclude that PRC is a functional relative of PGC-1 that operates through NRF-1 and possibly other activators in response to proliferative signals.
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Denis, Christopher M., Seth Chitayat, Michael J. Plevin, Feng Wang, Patrick Thompson, Shuang Liu, Holly L. Spencer, Mitsuhiko Ikura, David P. LeBrun, and Steven P. Smith. "Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1." Blood 120, no. 19 (November 8, 2012): 3968–77. http://dx.doi.org/10.1182/blood-2012-02-411397.
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Abstract E-proteins are critical transcription factors in B-cell lymphopoiesis. E2A, 1 of 3 E-protein–encoding genes, is implicated in the induction of acute lymphoblastic leukemia through its involvement in the chromosomal translocation 1;19 and consequent expression of the E2A-PBX1 oncoprotein. An interaction involving a region within the N-terminal transcriptional activation domain of E2A-PBX1, termed the PCET motif, which has previously been implicated in E-protein silencing, and the KIX domain of the transcriptional coactivator CBP/p300, critical for leukemogenesis. However, the structural details of this interaction remain unknown. Here we report the structure of a 1:1 complex between PCET motif peptide and the KIX domain. Residues throughout the helical PCET motif that contact the KIX domain are important for both binding KIX and bone marrow immortalization by E2A-PBX1. These results provide molecular insights into E-protein–driven differentiation of B-cells and the mechanism of E-protein silencing, and reveal the PCET/KIX interaction as a therapeutic target for E2A-PBX1–induced leukemia.
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Yang, Ke, Robyn L. Stanfield, Maria A. Martinez-Yamout, H. Jane Dyson, Ian A. Wilson, and Peter E. Wright. "Structural basis for cooperative regulation of KIX-mediated transcription pathways by the HTLV-1 HBZ activation domain." Proceedings of the National Academy of Sciences 115, no. 40 (September 19, 2018): 10040–45. http://dx.doi.org/10.1073/pnas.1810397115.
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The human T cell leukemia virus I basic leucine zipper protein (HTLV-1 HBZ) maintains chronic viral infection and promotes leukemogenesis through poorly understood mechanisms involving interactions with the KIX domain of the transcriptional coactivator CBP and its paralog p300. The KIX domain binds regulatory proteins at the distinct MLL and c-Myb/pKID sites to form binary or ternary complexes. The intrinsically disordered N-terminal activation domain of HBZ (HBZ AD) deregulates cellular signaling pathways by competing directly with cellular and viral transcription factors for binding to the MLL site and by allosterically perturbing binding of the transactivation domain of the hematopoietic transcription factor c-Myb. Crystal structures of the ternary KIX:c-Myb:HBZ complex show that the HBZ AD recruits two KIX:c-Myb entities through tandem amphipathic motifs (L/V)(V/L)DGLL and folds into a long α-helix upon binding. Isothermal titration calorimetry reveals strong cooperativity in binding of the c-Myb activation domain to the KIX:HBZ complex and in binding of HBZ to the KIX:c-Myb complex. In addition, binding of KIX to the two HBZ (V/L)DGLL motifs is cooperative; the structures suggest that this cooperativity is achieved through propagation of the HBZ α-helix beyond the first binding motif. Our study suggests that the unique structural flexibility and the multiple interaction motifs of the intrinsically disordered HBZ AD are responsible for its potency in hijacking KIX-mediated transcription pathways. The KIX:c-Myb:HBZ complex provides an example of cooperative stabilization in a transcription factor:coactivator network and gives insights into potential mechanisms through which HBZ dysregulates hematopoietic transcriptional programs and promotes T cell proliferation.
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Ernst, Patricia, Jing Wang, Mary Huang, Richard H. Goodman, and Stanley J. Korsmeyer. "MLL and CREB Bind Cooperatively to the Nuclear Coactivator CREB-Binding Protein." Molecular and Cellular Biology 21, no. 7 (April 1, 2001): 2249–58. http://dx.doi.org/10.1128/mcb.21.7.2249-2258.2001.
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ABSTRACT A fragment of the mixed-lineage leukemia (MLL) gene (Mll, HRX, ALL-1) was identified in a yeast genetic screen designed to isolate proteins that interact with the CREB–CREB-binding protein (CBP) complex. When tested for binding to CREB or CBP individually, this MLL fragment interacted directly with CBP, but not with CREB. In vitro binding experiments refined the minimal region of interaction to amino acids 2829 to 2883 of MLL, a potent transcriptional activation domain, and amino acids 581 to 687 of CBP (the CREB-binding or KIX domain). The transactivation activity of MLL was dependent on CBP, as either adenovirus E1A expression, which inhibits CBP activity, or alteration of MLL residues important for CBP interaction proved effective at inhibiting MLL-mediated transactivation. Single amino acid substitutions within the MLL activation domain revealed that five hydrophobic residues, potentially forming a hydrophobic face of an amphipathic helix, were critical for the interaction of MLL with CBP. Using purified components, we found that the MLL activation domain facilitated the binding of CBP to phosphorylated CREB. In contrast with paradigms in which factors compete for limiting quantities of CBP, these results reveal that two distinct transcription factor activation domains can cooperatively target the same motif on CBP.
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Li, Feng-Qian, Adaobi Mofunanya, Kimberley Harris, and Ken-Ichi Takemaru. "Chibby cooperates with 14-3-3 to regulate β-catenin subcellular distribution and signaling activity." Journal of Cell Biology 181, no. 7 (June 23, 2008): 1141–54. http://dx.doi.org/10.1083/jcb.200709091.
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β-Catenin functions in both cell–cell adhesion and as a transcriptional coactivator in the canonical Wnt pathway. Nuclear accumulation of β-catenin is the hallmark of active Wnt signaling and is frequently observed in human cancers. Although β-catenin shuttles in and out of the nucleus, the molecular mechanisms underlying its translocation remain poorly understood. Chibby (Cby) is an evolutionarily conserved molecule that inhibits β-catenin–mediated transcriptional activation. Here, we identified 14-3-3ε and 14-3-3ζ as Cby-binding partners using affinity purification/mass spectrometry. 14-3-3 proteins specifically recognize serine 20 within the 14-3-3–binding motif of Cby when phosphorylated by Akt kinase. Notably, 14-3-3 binding results in sequestration of Cby into the cytoplasm. Moreover, Cby and 14-3-3 form a stable tripartite complex with β-catenin, causing β-catenin to partition into the cytoplasm. Our results therefore suggest a novel paradigm through which Cby acts in concert with 14-3-3 proteins to facilitate nuclear export of β-catenin, thereby antagonizing β-catenin signaling.
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Guidez, Fabien, Louise Howell, Mark Isalan, Marek Cebrat, Rhoda M. Alani, Sarah Ivins, Itsaso Hormaeche, et al. "Histone Acetyltransferase Activity of p300 Is Required for Transcriptional Repression by the Promyelocytic Leukemia Zinc Finger Protein." Molecular and Cellular Biology 25, no. 13 (July 1, 2005): 5552–66. http://dx.doi.org/10.1128/mcb.25.13.5552-5566.2005.
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ABSTRACT Histone acetyltransferase (HAT) activities of proteins such as p300, CBP, and P/CAF play important roles in activation of gene expression. We now show that the HAT activity of p300 can also be required for down-regulation of transcription by a DNA binding repressor protein. Promyelocytic leukemia zinc finger (PLZF), originally identified as a fusion with retinoic acid receptor alpha in rare cases of all-trans-retinoic acid-resistant acute promyelocytic leukemia, is a transcriptional repressor that recruits histone deacetylase-containing corepressor complexes to specific DNA binding sites. PLZF associates with p300 in vivo, and its ability to repress transcription is specifically dependent on HAT activity of p300 and acetylation of lysines in its C-terminal C2-H2 zinc finger motif. An acetylation site mutant of PLZF does not repress transcription and is functionally deficient in a colony suppression assay despite retaining its abilities to interact with corepressor/histone deacetylase complexes. This is due to the fact that acetylation of PLZF activates its ability to bind specific DNA sequences both in vitro and in vivo. Taken together, our results indicate that a histone deacetylase-dependent transcriptional repressor can be positively regulated through acetylation and point to an unexpected role of a coactivator protein in transcriptional repression.
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Yang, Chih-Chao, Hillary K. Graves, Ivan M. Moya, Chunyao Tao, Fisun Hamaratoglu, Andrew B. Gladden, and Georg Halder. "Differential regulation of the Hippo pathway by adherens junctions and apical–basal cell polarity modules." Proceedings of the National Academy of Sciences 112, no. 6 (January 26, 2015): 1785–90. http://dx.doi.org/10.1073/pnas.1420850112.
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Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical–basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non–cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non–cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.
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Zhang, Feng, Jiyuan Ke, Li Zhang, Rongzhi Chen, Koichi Sugimoto, Gregg A. Howe, H. Eric Xu, Mingguo Zhou, Sheng Yang He, and Karsten Melcher. "Structural insights into alternative splicing-mediated desensitization of jasmonate signaling." Proceedings of the National Academy of Sciences 114, no. 7 (January 30, 2017): 1720–25. http://dx.doi.org/10.1073/pnas.1616938114.
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Jasmonate ZIM-domain (JAZ) transcriptional repressors play a key role in regulating jasmonate (JA) signaling in plants. Below a threshold concentration of jasmonoyl isoleucine (JA-Ile), the active form of JA, the C-terminal Jas motif of JAZ proteins binds MYC transcription factors to repress JA signaling. With increasing JA-Ile concentration, the Jas motif binds to JA-Ile and the COI1 subunit of the SCFCOI1 E3 ligase, which mediates ubiquitination and proteasomal degradation of JAZ repressors, resulting in derepression of MYC transcription factors. JA signaling subsequently becomes desensitized, in part by feedback induction of JAZ splice variants that lack the C-terminal Jas motif but include an N-terminal cryptic MYC-interaction domain (CMID). The CMID sequence is dissimilar to the Jas motif and is incapable of recruiting SCFCOI1, allowing CMID-containing JAZ splice variants to accumulate in the presence of JA and to re-repress MYC transcription factors as an integral part of reestablishing signal homeostasis. The mechanism by which the CMID represses MYC transcription factors remains elusive. Here we describe the crystal structure of the MYC3–CMIDJAZ10 complex. In contrast to the Jas motif, which forms a single continuous helix when bound to MYC3, the CMID adopts a loop–helix–loop–helix architecture with modular interactions with both the Jas-binding groove and the backside of the Jas-interaction domain of MYC3. This clamp-like interaction allows the CMID to bind MYC3 tightly and block access of MED25 (a subunit of the Mediator coactivator complex) to the MYC3 transcriptional activation domain, shedding light on the enigmatic mechanism by which JAZ splice variants desensitize JA signaling.
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Martini, Alessandro, Gino Marioni, Elisabetta Zanoletti, Rocco Cappellesso, Roberto Stramare, Elena Fasanaro, Chiara Faccioli, et al. "Yap, Taz and Areg Expression in Eighth Cranial Nerve Schwannoma." International Journal of Biological Markers 32, no. 3 (July 2017): 319–24. http://dx.doi.org/10.5301/ijbm.5000263.
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Background Although the diagnosis and treatment of eighth cranial nerve (VIII CN) schwannoma (acoustic neuroma) has improved over the years, no factors capable of predicting tumor growth have been identified as yet. This study is a preliminary investigation of the expression in sporadic VIII CN schwannomas of Yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), and amphiregulin (AREG), a direct target gene of YAP and TAZ. The expression of YAP, TAZ and AREG was correlated with the volumetric dimensions of tumors on contrast-enhanced magnetic resonance imaging (ceMRI). Methods YAP, TAZ and AREG expression was assessed immunohistochemically in surgical specimens of 36 consecutive sporadic VIII CN schwannomas. 3D reconstructions of the tumors and their corresponding volumes in cm3 were obtained from measurements on ceMRI images using the OsiriX® software. Results We found a significant direct correlation between TAZ expression and VIII CN schwannoma volumes on latest preoperative ceMRI (p<0.0003). Mean TAZ expression was also significantly higher in VIII CN schwannomas with a volume ≥2.1 cm3 than in those with a volume <2.1 cm3 (p<0.0018). No significant correlations emerged for YAP or AREG expression and VIII CN schwannoma volume. Conclusions The immunohistochemical expression of TAZ (but not YAP or AREG) correlated significantly with schwannoma volume measured on ceMRI. Further investigations are needed to identify the biological factors influencing tumor proliferation (ideally secreted proteins like AREG) that might be detected using non-invasive approaches (i.e., blood samples).
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Noguchi, Satoshi, Akira Saito, and Takahide Nagase. "YAP/TAZ Signaling as a Molecular Link between Fibrosis and Cancer." International Journal of Molecular Sciences 19, no. 11 (November 20, 2018): 3674. http://dx.doi.org/10.3390/ijms19113674.
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Tissue fibrosis is a pathological condition that is associated with impaired epithelial repair and excessive deposition of extracellular matrix (ECM). Fibrotic lesions increase the risk of cancer in various tissues, but the mechanism linking fibrosis and cancer is unclear. Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are core components of the Hippo pathway, which have multiple biological functions in the development, homeostasis, and regeneration of tissues and organs. YAP/TAZ act as sensors of the structural and mechanical features of the cell microenvironment. Recent studies have shown aberrant YAP/TAZ activation in both fibrosis and cancer in animal models and human tissues. In fibroblasts, ECM stiffness mechanoactivates YAP/TAZ, which promote the production of profibrotic mediators and ECM proteins. This results in tissue stiffness, thus establishing a feed-forward loop of fibroblast activation and tissue fibrosis. In contrast, in epithelial cells, YAP/TAZ are activated by the disruption of cell polarity and increased ECM stiffness in fibrotic tissues, which promotes the proliferation and survival of epithelial cells. YAP/TAZ are also involved in the epithelial–mesenchymal transition (EMT), which contributes to tumor progression and cancer stemness. Importantly, the crosstalk with transforming growth factor (TGF)-β signaling and Wnt signaling is essential for the profibrotic and tumorigenic roles of YAP/TAZ. In this article, we review the latest advances in the pathobiological roles of YAP/TAZ signaling and their function as a molecular link between fibrosis and cancer.
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Manna, Pulak R., and Douglas M. Stocco. "Crosstalk of CREB and Fos/Jun on a single cis-element: transcriptional repression of the steroidogenic acute regulatory protein gene." Journal of Molecular Endocrinology 39, no. 4 (October 2007): 261–77. http://dx.doi.org/10.1677/jme-07-0065.
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AbstractTranscriptional regulation of the steroidogenic acute regulatory (StAR) protein gene by cAMP-dependent mechanisms occurs in the absence of a consensus cAMP-response element (CRE; TGACGTCA) and is mediated by several sequence-specific transcription factors. We previously identified three CRE-like sites (within the −151/−1 bp cAMP-responsive region of the mouse StAR gene), of which the CRE2 site overlaps with an activator protein-1 (AP-1) motif (TGACTGA, designated as CRE2/AP-1) that can bind both CRE and AP-1 DNA-binding proteins. The present studies were aimed at exploring the functional crosstalk between CREB (CRE-binding protein) and cFos/cJun (AP-1 family members) on the CRE2/AP-1 element and its role in regulating transcription of the StAR gene. Using MA-10 mouse Leydig tumor cells, we demonstrate that the CRE and AP-1 families of proteins interact with the CRE2/AP-1 sequence. CREB, cFos, and cJun proteins were found to bind to the CRE2/AP-1 motif but not the CRE1 and CRE3 sites. Treatment with the cAMP analog (Bu)2cAMP augmented phosphorylation of CREB (Ser133), cFos (Thr325), and cJun (ser73). Chromatin immunoprecipitation studies revealed that the induction of CREB, cFos, and cJun by (Bu)2cAMP was correlated with protein–DNA interactions and recruitment of the coactivator CREB-binding protein (CBP) to the StAR promoter. EMSA studies employing CREB and cFos/cJun proteins demonstrated competition between these factors for binding to the CRE2/AP-1 motif. Transfection of cells containing the −151/−1 StAR reporter with CREB and cFos/cJun resulted in trans-repression of the StAR gene, an event tightly associated with CBP, demonstrating that both CREB and Fos/Jun compete with each other for binding with limited amounts of intracellular CBP. Overexpression of adenovirus E1A, which binds and inactivates CBP, markedly suppressed StAR gene expression. Ectopic expression of CBP eliminated the repression of the StAR gene by E1A and potentiated the activity of CREB and cFos/cJun on StAR promoter responsiveness. These findings identify molecular events involved in crosstalk between CREB and cFos/cJun, which confer both gain and loss of function on a single cis-element in fine-tuning of the regulatory events involved in transcription of the StAR gene.
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Gachon, Frederic, Sabine Thebault, Annick Peleraux, Christian Devaux, and Jean-Michel Mesnard. "Molecular Interactions Involved in the Transactivation of the Human T-Cell Leukemia Virus Type 1 Promoter Mediated by Tax and CREB-2 (ATF-4)." Molecular and Cellular Biology 20, no. 10 (May 15, 2000): 3470–81. http://dx.doi.org/10.1128/mcb.20.10.3470-3481.2000.
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ABSTRACT The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates viral transcription through three 21-bp repeats located in the U3 region of the HTLV-1 long terminal repeat and called Tax-responsive elements (TxREs). Each TxRE contains nucleotide sequences corresponding to imperfect cyclic AMP response elements (CRE). In this study, we demonstrate that the bZIP transcriptional factor CREB-2 is able to bind in vitro to the TxREs and that CREB-2 binding to each of the 21-bp motifs is enhanced by Tax. We also demonstrate that Tax can weakly interact with CREB-2 bound to a cellular palindromic CRE motif such as that found in the somatostatin promoter. Mutagenesis of Tax and CREB-2 demonstrates that both N- and C-terminal domains of Tax and the C-terminal region of CREB-2 are required for direct interaction between the two proteins. In addition, the Tax mutant M47, defective for HTLV-1 activation, is unable to form in vitro a ternary complex with CREB-2 and TxRE. In agreement with recent results suggesting that Tax can recruit the coactivator CREB-binding protein (CBP) on the HTLV-1 promoter, we provide evidence that Tax, CREB-2, and CBP are capable of cooperating to stimulate viral transcription. Taken together, our data highlight the major role played by CREB-2 in Tax-mediated transactivation.
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Talukder, Amjad H., Anupama Gururaj, Sandip K. Mishra, Ratna K. Vadlamudi, and Rakesh Kumar. "Metastasis-Associated Protein 1 Interacts with NRIF3, an Estrogen-Inducible Nuclear Receptor Coregulator." Molecular and Cellular Biology 24, no. 15 (August 1, 2004): 6581–91. http://dx.doi.org/10.1128/mcb.24.15.6581-6591.2004.
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ABSTRACT The transcriptional activity of estrogen receptor alpha (ER-α) is modified by regulatory action and interactions of coactivators and corepressors. Recent studies have shown that the metastasis-associated protein 1 (MTA1) represses estrogen receptor element (ERE)-driven transcription in breast cancer cells. With a yeast two-hybrid screen to clone MTA1-interacting proteins, we identified a known nuclear receptor coregulator (NRIF3) as an MTA1-binding protein. NRIF3 interacted with MTA1 both in vitro and in vivo. NRIF3 bound to the C-terminal region of MTA1, while MTA1 bound to the N-terminal region of NRIF3, containing one nuclear receptor interaction LXXLL motif. We showed that NRIF3 is an ER coactivator, hyperstimulated ER transactivation functions, and associated with the endogenous ER and its target gene promoter. MTA1 repressed NRIF3-mediated stimulation of ERE-driven transcription and interfered with NRIF3's association with the ER target gene chromatin. In addition, NRIF3 deregulation enhanced the responsiveness of breast cancer cells to estrogen-induced stimulation of growth and anchorage independence. Furthermore, we found that NRIF3 is an estrogen-inducible gene and activated ER associated with the ER response element in the NRIF3 gene promoter. These findings suggest that NRIF3, an MTA1-interacting protein, is an estrogen-inducible gene and that regulatory interactions between MTA1 and NRIF3 might be important in modulating the sensitivity of breast cancer cells to estrogen.
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Bayly, Richard, Takayuki Murase, Brandy D. Hyndman, Rachel Savage, Salima Nurmohamed, Kim Munro, Richard Casselman, Steven P. Smith, and David P. LeBrun. "Critical Role for a Single Leucine Residue in Leukemia Induction by E2A-PBX1." Molecular and Cellular Biology 26, no. 17 (September 1, 2006): 6442–52. http://dx.doi.org/10.1128/mcb.02025-05.
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ABSTRACT In roughly 5% of cases of acute lymphoblastic leukemia, a chromosomal translocation leads to expression of the oncogenic protein E2A-PBX1. The N-terminal portion of E2A-PBX1, encoded by the E2A gene, is identical in sequence to the corresponding portion of the E proteins E12/E47 and includes transcriptional activation domains. The C terminus consists of most of the HOX interacting transcription factor PBX1, including its DNA-binding homeodomain. Structure-function correlative experiments have suggested that oncogenesis by E2A-PBX1 requires an activation domain, called AD1, at the extreme N terminus. We recently demonstrated that a potentially helical portion of AD1 interacts directly with the transcriptional coactivator protein cyclic AMP response element-binding protein (CBP) and that this interaction is essential in the immortalization of primary bone marrow cells in tissue culture. Here we show that a conserved LXXLL motif within AD1 is required in the interaction between E2A-PBX1 and the KIX domain of CBP. We show by circular dichroism spectroscopy that the LXXLL-containing portion of AD1 undergoes a helical transition upon interacting with the KIX domain and that amino acid substitutions that prevent helix formation prevent both the KIX interaction and cell immortalization by E2A-PBX1. Perhaps most strikingly, substitution of a single, conserved leucine residue (L20) within the LXXLL motif impairs leukemia induction in mice after transplantation with E2A-PBX1-expressing bone marrow. The KIX domain of CBP mediates well-characterized interactions with several transcription factors of relevance to leukemia induction. Circumstantial evidence suggests that the side chain of L20 might interact with a deep hydrophobic pocket in the KIX domain. Therefore, our results serve to identify a potential new drug target.
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Yuan, Li, Mengmeng Zhou, Harpreet S. Wasan, Kai Zhang, Zhaoyi Li, Kaibo Guo, Fengfei Shen, Minhe Shen, and Shanming Ruan. "Jiedu Sangen Decoction Inhibits the Invasion and Metastasis of Colorectal Cancer Cells by Regulating EMT through the Hippo Signaling Pathway." Evidence-Based Complementary and Alternative Medicine 2019 (June 25, 2019): 1–10. http://dx.doi.org/10.1155/2019/1431726.
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Colorectal cancer (CRC) is one of the most common malignant tumors affecting the digestive tract. Moreover, the invasion and metastasis of CRC are the main reason therapy is usually inefficient. Decreased intercellular adhesion and enhanced cell motility induced by epithelial-mesenchymal transition (EMT) provide the basic conditions for the invasion and metastasis of the epithelial tumor cells of CRC. The Jiedu Sangen Decoction (JSD) is a prescription that has been used for more than 50 years in the treatment of CRC in the Zhejiang Hospital of Traditional Chinese Medicine. The aim of this study was to investigate the mechanism of JSD-triggered inhibition of invasion and metastasis in colon cancer. In vitro, the EMT model of the SW480 cells was induced by using epithelial growth factor (50 ng/mL). In vivo, the murine model of liver metastasis was constructed by inoculating mice with the SW480 cells. The effects of JSD on cell migration, invasion, and proliferation were determined using the transwell assay and CCK-8 assay. Moreover, the proteins related to the EMT process and the Hippo signaling pathway in the cancerous tissues and cell lines were determined by western blotting and immunostaining. JSD could significantly inhibit the proliferation, migration, and invasion of CRC cells and reverse their EMT status (all, P < 0.05). Moreover, after intervention with JSD, the levels of E-Cadherin (E-cad) increased, whereas the expression levels of N-Cadherin (N-cad), Yes-associated protein (YAP), and the transcriptional coactivator with the PDZ-binding motif (TAZ) decreased in both the SW480 cells and the tumor tissues. In summary, JSD reversed EMT and inhibited the invasion and metastasis of CRC cells through the Hippo signaling pathway.
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Pattnaik, Bodhiswata, Sweta Mohanty, Surya Narayan Das, Rachna Rath, Archana Bhatta, and Sourav Mishra. "Immunohistochemical evaluation of yes-associated protein molecule in the odontogenic epithelium of different histopathological variants of ameloblastoma and unicystic ameloblastoma." Journal of Oral and Maxillofacial Pathology 28, no. 1 (January 2024): 49–55. http://dx.doi.org/10.4103/jomfp.jomfp_215_23.
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Background: Ameloblastoma is one of the major odontogenic neoplasms with an invasive and recurrence potential. Its tumourigenesis and proliferative capacity can be attributed to the activation or inactivation of certain molecular signalling pathways. Hippo signalling pathway is known to regulate diverse physiological processes related to mitosis and organ growth and is an emerging tumour suppressor pathway, the dysfunction of which is implicated in various diseases including cancers. Yes-associated protein1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the downstream effectors in the Hippo cascade, which on nuclear activation leads to cellular proliferation in various tumours. Aim: The current study was undertaken to evaluate the expression of YAP in various histopathological variants of ameloblastoma and unicystic ameloblastoma. Materials and Methods: Fifty formalin-fixed paraffin-embedded tissue samples of histopathologically diagnosed cases of ameloblastoma, and 10 histopathologically diagnosed cases of unicystic ameloblastoma were obtained from the departmental archives to evaluate the immunohistochemical expression of YAP both manually and by software analysis. Results: More than 90% of cases of conventional ameloblastoma and unicystic ameloblastoma elicited positive expression of YAP. No statistical difference was found among different histopathological variants of conventional ameloblastoma. Significant difference between the means of all four quantitative score groups was observed. Conclusion: In view of the modulating effect of YAP in tumourigenesis and its higher expression in ameloblastoma, further exploration of this molecule appears to be a promising area of research.
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Goradia, Nishit, Stefan Werner, Edukondalu Mullapudi, Gunhild von Amsberg, Klaus Pantel, and Matthias Wilmanns. "Abstract 3023: Master corepressor inactivation through oncogene suppressor RAI2 mediated polymerization." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3023. http://dx.doi.org/10.1158/1538-7445.am2024-3023.
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Abstract Imbalanced transcription of a large number of genes can be caused at various levels, ranging from alterations in individual transcription factors to dysfunctional corepressor and coactivator complexes [1]. C-terminal binding proteins (CtBPs) are ubiquitous master transcriptional coregulators associated with the Polycomb Repressive Complex 2 (PRC2), with essential functions in the development and oncogenesis of various tumor entities, including breast cancer and prostate cancer (PC) [2,3]. As CtBPs bind to short linear PxDLS-like sequence motifs (SLiMs), the presence of such motifs in tandem on the putative metastasis suppressor RAI2 [4] suggested a previously undiscovered dual interaction with CtBPs. Here, we show that RAI2 induces CtBP polymerization through well-ordered filaments of stacked tetrameric CtBP layers, as illustrated by a high-resolution single particle cryo electron microscopy structure. These filaments are mirrored by RAI2-mediated CtBP nuclear foci and relief of CtBP corepressor function in RAI2-expressing cancer cells. Analyses of a diverse PC patient cohort revealed a substantial decrease in RAI2 in the aggressive subtypes, suggesting a pivotal role of RAI2 in the transition to androgen receptor signaling-independent progression. Taken together, our data demonstrate a previously unknown mechanism of multivalent short linear sequence motif-induced polymerization. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions. The specific properties of these repeated interactions open up new therapeutic opportunities. References [1] Lee, T.I. & Young, R.A. Transcriptional regulation and its misregulation in disease. Cell 152, 1237-51 (2013). [2] Di, L.J. et al. Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat Commun 4, 1449 (2013). [3] Wang, R. et al. Role of transcriptional corepressor CtBP1 in prostate cancer progression. Neoplasia 14, 905-14 (2012). [4] Werner, S. et al. Suppression of early hematogenous dissemination of human breast cancer cells to bone marrow by retinoic Acid-induced 2. Cancer Discov 5, 506-19 (2015). Citation Format: Nishit Goradia, Stefan Werner, Edukondalu Mullapudi, Gunhild von Amsberg, Klaus Pantel, Matthias Wilmanns. Master corepressor inactivation through oncogene suppressor RAI2 mediated polymerization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3023.
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Mana-Capelli, Sebastian, and Dannel McCollum. "Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote Hippo signaling." Journal of Biological Chemistry 293, no. 47 (September 28, 2018): 18230–41. http://dx.doi.org/10.1074/jbc.ra118.004187.
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The Hippo pathway controls cell proliferation, differentiation, and survival by regulating the Yes-associated protein (YAP) transcriptional coactivator in response to various stimuli, including the mechanical environment. The major YAP regulators are the LATS1/2 kinases, which phosphorylate and inhibit YAP. LATS1/2 are activated by phosphorylation on a hydrophobic motif (HM) outside of the kinase domain by MST1/2 and other kinases. Phosphorylation of the HM motif then triggers autophosphorylation of the kinase in the activation loop to fully activate the kinase, a process facilitated by MOB1. The angiomotin family of proteins (AMOT, AMOTL1, and AMOTL2) bind LATS1/2 and promote its kinase activity and YAP phosphorylation through an unknown mechanism. Here we show that angiomotins increase Hippo signaling through multiple mechanisms. We found that, by binding LATS1/2, SAV1, and YAP, angiomotins function as a scaffold that connects LATS1/2 to both its activator SAV1–MST1 and its target YAP. Deletion of all three angiomotins reduced the association of LATS1 with SAV1–MST1 and decreased MST1/2-mediated LATS1/2-HM phosphorylation. Angiomotin deletion also reduced LATS1/2's ability to associate with and phosphorylate YAP. In addition, we found that angiomotins have an unexpected function along with MOB1 to promote autophosphorylation of LATS1/2 on the activation loop motif independent of HM phosphorylation. These results indicate that angiomotins enhance Hippo signaling by stimulating LATS1/2 autophosphorylation and by connecting LATS1/2 with both its activator SAV1–MST1/2 and its substrate YAP.
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Alen, Philippe, Frank Claessens, Guido Verhoeven, Wilfried Rombauts, and Ben Peeters. "The Androgen Receptor Amino-Terminal Domain Plays a Key Role in p160 Coactivator-Stimulated Gene Transcription." Molecular and Cellular Biology 19, no. 9 (September 1, 1999): 6085–97. http://dx.doi.org/10.1128/mcb.19.9.6085.
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ABSTRACT Steroid receptors are conditional transcription factors that, upon binding to their response elements, regulate the expression of target genes via direct protein interactions with transcriptional coactivators. We have analyzed the functional interactions between the androgen receptor (AR) and 160-kDa nuclear receptor coactivators. Upon overexpression in mammalian cells, these coactivators enhance the transcriptional activity of both the amino-terminal domain (NTD) and the ligand-binding domain (LBD) of the AR. The coactivator activity for the LBD is strictly ligand-controlled and depends on the nature of the DNA-binding domain to which it is fused. We demonstrate that the NTD physically interacts with coactivators and with the LBD and that this interaction, like the functional interaction between the LBD and p160 coactivators, relies on the activation function 2 (AF2) core domain. The mutation of a highly conserved lysine residue in the predicted helix 3 of the LBD (K720A), however, blunts the functional interaction with coactivators but not with the NTD. Moreover, this mutation does not affect the transcriptional activity of the full-size AR. A mutation in the NTD of activation function AF1a (I182A/L183A), which dramatically impairs the activity of the AR, has no effect on the intrinsic transcriptional activity of the NTD but interferes with the cooperation between the NTD and the LBD. Finally, p160 proteins in which the three LXXLL motifs are mutated retain most of their coactivator activity for the full-size AR, although they are no longer functional for the isolated LBD. Together, these data suggest that in the native AR the efficient recruitment of coactivators requires a functional association of the NTD with the LBD and that the binding of coactivators occurs primarily through the NTD.
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Anafi, Mordecai, Yong-Fan Yang, Nick A. Barlev, Manjapra V. Govindan, Shelley L. Berger, Tauseef R. Butt, and Paul G. Walfish. "GCN5 and ADA Adaptor Proteins Regulate Triiodothyronine/GRIP1 and SRC-1 Coactivator-Dependent Gene Activation by the Human Thyroid Hormone Receptor." Molecular Endocrinology 14, no. 5 (May 1, 2000): 718–32. http://dx.doi.org/10.1210/mend.14.5.0457.
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Abstract We have used yeast genetics and in vitro protein-protein interaction experiments to explore the possibility that GCN5 (general control nonrepressed protein 5) and several other ADA (alteration/deficiency in activation) adaptor proteins of the multimeric SAGA complex can regulate T3/GRIP1 (glucocorticoid receptor interacting protein 1) and SRC-1 (steroid receptor coactivator-1) coactivator-dependent activation of transcription by the human T3 receptor β1 (hTRβ1). Here, we show that in vivo activation of a T3/GRIP1 or SRC-1 coactivator-dependent T3 hormone response element by hTRβ1 is dependent upon the presence of yeast GCN5, ADA2, ADA1, or ADA3 adaptor proteins and that the histone acetyltransferase (HAT) domains and bromodomain (BrD) of yGCN5 must be intact for maximal activation of transcription. We also observed that hTRβ1 can bind directly to yeast or human GCN5 as well as hADA2, and that the hGCN5387−837 sequence could bind directly to either GRIP1 or SRC-1 coactivator. Importantly, the T3-dependent binding of hTRβ1to hGCN5387−837 could be markedly increased by the presence of GRIP1 or SRC1. Mutagenesis of GRIP1 nuclear receptor (NR) Box II and III LXXLL motifs also substantially decreased both in vivo activation of transcription and in vitro T3-dependent binding of hTRβ1 to hGCN5. Taken together, these experiments support a multistep model of transcriptional initiation wherein the binding of T3 to hTRβ1 initiates the recruitment of p160 coactivators and GCN5 to form a trimeric transcriptional complex that activates target genes through interactions with ADA/SAGA adaptor proteins and nucleosomal histones.
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Tzachanis, Dimitrios, Alla Berezovskaya, Esther M. Lafuente, Lequn Li, Gordon J. Freeman, and Vassiliki A. Boussiotis. "The E3 Ubiquitin Ligase TRIM36, a Transcriptional Target of Tob, Is Expressed in Anergic T Cells and Mediates Unresponsiveness through Proteolysis of Signaling Proteins PLC- γ1 and PKC-𝛉." Blood 104, no. 11 (November 16, 2004): 113. http://dx.doi.org/10.1182/blood.v104.11.113.113.
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Abstract Ligation of the T cell receptor (TCR) and costimulatory receptors leads to cytokine secretion and clonal expansion, whereas ligation of TCR alone leads to anergy. We have previously determined that anergic cells express Tob, a member of the novel APRO gene family, which inhibits T cell activation. The precise molecular mechanisms via which Tob mediates its effects in T cells are not fully understood. Tob functions as transcriptional coactivator and enhances DNA binding of Smads. Therefore, Tob may regulate de novo mRNA synthesis or gene transcription. To identify genes that are induced by Tob, Jurkat T cells that lack endogenous Tob, were transfected with Tob cDNA or empty vector and differential gene expression was determined by suppression subtractive hybridization. TRIM36 was one of the genes induced by Tob. TRIM36 is a RING finger E3 ubiquitin ligase. It belongs to a recently identified tripartite motif (TRIM) gene family which also includes Pyrin/Marenosrtin, MID1, MUL, PML, RFP and TIF1, proteins implicated in familial human diseases and cancer. E3 proteins confer substrate specificity to the ubiquitin system. Previous studies have shown that the trancriptional profile of anergic cells includes the E3 ubiquitin ligases Cbl-b, GRAIL and Itch. Therefore, the finding that Tob, a transcriptional regulator expressed in anergic cells, induces expression of TRIM36 E3 ubiquitin ligase is very intriguing. Northern blot analysis confirmed that TRIM36 mRNA was selectively upregulated in anergic T cells. To determine the role of TRIM36 on IL-2 gene transcription, Jurkat T cells were transfected with full-length TRIM36 cDNA along with the IL-2 promoter/enhancer cDNA (2kb) linked to the luciferase gene. TRIM36 inhibited CD3+CD28-mediated IL-2 transcription by 90%. Interestingly, when cells were stimulated with PMA+Ionomycin, which bypass the TCR proximal signals, IL-2 transcription was almost unaffected. These results prompted us to search for candidate ubiquitination substrates among signaling molecules that have a critical role on TCR-mediated T cell activation and IL-2 transcription. Previous studies have shown that among T cell signaling molecules, TCRζ, ZAP70, PLC-γ1 and PKC-𝛉 undergo ubiquitin-targeted degradation. For this reason, we investigated whether any of these proteins might be substrates for TRIM36-mediated ubiquitination. V5-tagged TRIM36 or empty vector was expressed in Jurkat T cells followed by stimulation with anti-CD3+anti-CD28 mAbs in the presence of ubiquitin aldehyde that prevents substrate deubiquitination. Immunoblot with antibodies specific for TCR ζ, ZAP70, PLC-γ1 and PKC-𝛉 showed that expression of PLC-γ1 and PKC-𝛉 was selectively reduced in the presence of TRIM36. Immunoprecipitation with V5 mAb followed by immunoblot with substrate-specific antibodies revealed that PLC- γ1 and PKC-𝛉 coprecipitated with TRIM36. Immunoblot with ubiquitin-specific antibody revealed that PLC-γ1 and PKC- 𝛉 were substrates for ubiquitination by TRIM36. Our results show that at least one molecular mechanism via which Tob mediates its inhibitory effect on T cell activation involves the induction of TRIM36 ubiquitin ligase, which mediates degradation of two key signaling proteins, PLC- γ1 and PKC-𝛉. Moreover, these results suggest that TRIM36 may represent a novel target of molecular intervention for induction of transplantation tolerance.
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Strakova, Zuzana, Jennifer Reed, and Ivanna Ihnatovych. "Human Transcriptional Coactivator with PDZ-Binding Motif (TAZ) Is Downregulated During Decidualization1." Biology of Reproduction 82, no. 6 (June 1, 2010): 1112–18. http://dx.doi.org/10.1095/biolreprod.109.081844.
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Powell, S. M., V. Christiaens, D. Voulgaraki, J. Waxman, F. Claessens, and C. L. Bevan. "Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in prostate." Endocrine-related cancer 11, no. 1 (March 2004): 117–30. http://dx.doi.org/10.1677/erc.0.0110117.
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The androgen receptor (AR) is a member of the nuclear receptor superfamily. These ligand-activated transcription factors usually contain two activation functions, a ligand-independent activation function 1(AF1) in the divergent N-terminal domain and a ligand-dependent AF2 in the more conserved C-terminal ligand-binding domain. To promote transcription from target promoters, DNA-bound nuclear receptors recruit coactivator proteins that promote transcription by modifying histones within nucleosomes, resulting in altered topology of chromatin to allow access of the basal transcriptional machinery, or stabilising the pre-initiation complex. It is well known that most coactivators interact with AF2 of many nuclear receptors via conserved, helical LxxLL motifs (where L is leucine and x is any amino acid). The AF2 of the AR is very weak, but we were able to demonstrate that its intrinsic ligand-dependent activity is potentiated by steroid receptor coactivator-1 (SRC1) and that this region interacts with coactivators via LxxLL motifs. However, a mutant SRC1 coactivator with no functional LxxLL motifs was still able to potentiate AR activity. We found that SRC1 can also be recruited to (and increase activity of) AF1 of the AR via a conserved, glutamine-rich region. Point mutations within this region abolish SRC1 interaction with AF1 and also abolish or severely impair its ability to potentiate AR activity on all promoters tested. Thus the AR interacts with SRC1 via two different regions and the AF1 interaction is functionally the more important, although the contribution of the two interactions varies in a promoter-dependent fashion. SRC1 then potentiates receptor activity via recruitment of CBP/p300, a histone acetyltranferase. This is important in the context of prostate cancer as SRC1 and other coactivators including CBP are coexpressed with AR in the luminal epithelial cells of the prostate, where over 90% of prostate tumours arise. There is a need for effective second-line prostate cancer therapy aimed at blocking the AR pathway when anti-androgen therapy has failed. Since there is growing evidence that nuclear receptor cofactors may be implicated in the progression of hormone-dependent tumours to hormone-independent states, novel targets could include the interaction of AR with coactivator proteins. We suggest that the N-terminal interaction would be a more specific and effective target in the case of prostate cancer than the LxxLL/AF2 interaction.
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Mitani, Akihisa, Takahide Nagase, Kazunori Fukuchi, Hiroyuki Aburatani, Ryosuke Makita, and Hiroki Kurihara. "Transcriptional Coactivator with PDZ-binding Motif Is Essential for Normal Alveolarization in Mice." American Journal of Respiratory and Critical Care Medicine 180, no. 4 (August 15, 2009): 326–38. http://dx.doi.org/10.1164/rccm.200812-1827oc.
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Ortega, Ángel, Ivana Vera, Maria Diaz, Carla Navarro, Milagros Rojas, Wheeler Torres, Heliana Parra, Juan Salazar, Juan De Sanctis, and Valmore Bermúdez. "The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises." International Journal of Molecular Sciences 23, no. 1 (December 31, 2021): 430. http://dx.doi.org/10.3390/ijms23010430.
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The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways’ role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.
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Leers, Jörg, Eckardt Treuter, and Jan-Åke Gustafsson. "Mechanistic Principles in NR Box-Dependent Interaction between Nuclear Hormone Receptors and the Coactivator TIF2." Molecular and Cellular Biology 18, no. 10 (October 1, 1998): 6001–13. http://dx.doi.org/10.1128/mcb.18.10.6001.
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ABSTRACT Nuclear hormone receptors exert transcriptional activation of target genes upon hormone induction via interactions with the basal transcription machinery. This interaction is mediated by cofactors which physically bind to receptors, thereby acting as coactivators or corepressors leading to activation or repression, respectively. Here we report the screening for and cloning of a peroxisome proliferator receptor-interacting protein, the rat homolog of TIF2. By sequence comparison with the related coactivator SRC-1, we identified three short conserved motifs (NR boxes) in both proteins which are the putative binding sites of TIF2 to nuclear hormone receptors. We demonstrate here by generation of amino acid exchanges within the NR boxes that all three boxes located in the receptor interaction domain of TIF2 are necessary and sufficient for interaction. The three boxes individually can bind to hormone receptors but display preferences in binding for certain receptors. In addition, we show that the interaction domain of TIF2 can compete with other AF-2-dependent cofactors for binding to receptors. Finally, we demonstrate cooperative binding of two TIF2 molecules to a heterodimeric nuclear receptor complex even in the presence of only one cognate ligand, indicating an allosteric effect on the heterodimeric partner upon coactivator binding.
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Chen, Jianchun, Xiaoyong Wang, Qian He, and Raymond C. Harris. "TAZ is important for maintenance of the integrity of podocytes." American Journal of Physiology-Renal Physiology 322, no. 4 (April 1, 2022): F419—F428. http://dx.doi.org/10.1152/ajprenal.00426.2021.
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Podocytes play an important role in maintaining the integrity of the structure and function of the kidney. We observed that mice with selective deletion of transcriptional coactivator with PDZ-binding motif (TAZ) in podocytes developed proteinuria. TAZ is constitutively active and critical for expression of synaptopodin, zonula occludens-1, and zonula occludens-2 in podocytes. The findings of this study implicate TAZ as an important mediator of podocyte structural integrity and provide further insights into the role of Hippo-Yes-associated protein/TAZ in podocyte biology.
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Jeong, Mi Gyeong, Hyuna Song, Ji Hyun Shin, Hana Jeong, Hyo Kyeong Kim, and Eun Sook Hwang. "Transcriptional coactivator with PDZ-binding motif is required to sustain testicular function on aging." Aging Cell 16, no. 5 (June 14, 2017): 1035–42. http://dx.doi.org/10.1111/acel.12631.
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Miyajima, Chiharu, Yuki Kawarada, Yasumichi Inoue, Chiaki Suzuki, Kana Mitamura, Daisuke Morishita, Nobumichi Ohoka, Takeshi Imamura, and Hidetoshi Hayashi. "Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence." Cells 9, no. 1 (January 9, 2020): 171. http://dx.doi.org/10.3390/cells9010171.
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Transcriptional coactivator with a PDZ-binding motif (TAZ) is one of the mammalian orthologs of Drosophila Yorkie, a transcriptional coactivator of the Hippo pathway. TAZ has been suggested to function as a regulator that modulates the expression of cell proliferation and anti-apoptotic genes in order to stimulate cell proliferation. TAZ has also been associated with a poor prognosis in several cancers, including breast cancer. However, the physiological role of TAZ in tumorigenesis remains unclear. We herein demonstrated that TAZ negatively regulated the activity of the tumor suppressor p53. The overexpression of TAZ down-regulated p53 transcriptional activity and its downstream gene expression. In contrast, TAZ knockdown up-regulated p21 expression induced by p53 activation. Regarding the underlying mechanism, TAZ inhibited the interaction between p53 and p300 and suppressed the p300-mediated acetylation of p53. Furthermore, TAZ knockdown induced cellular senescence in a p53-dependent manner. These results suggest that TAZ negatively regulates the tumor suppressor functions of p53 and attenuates p53-mediated cellular senescence.